Pulmonary Involvement in Patients with Hematological Malignancies

Pulmonary Involvement in Patients with Hematological Malignancies

 

Élie Azoulay (Editor)

Pulmonary Involvement in Patients with Hematological Malignancies

Editor Élie Azoulay, M.D., Ph.D Service de Réanimation Médicale Hôpital Saint-Louis 1 avenue Claude Vellefaux, 75010, Paris France and Medical Intensive Care Units, Saint-Louis Hospital, Paris 7 University, Paris France [email protected]

ISBN  978-3-642-15741-7 e-ISBN  978-3-642-15742-4 DOI  10.1007/978-3-642-15742-4 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2011921694 © Springer-Verlag Berlin Heidelberg 2011 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: eStudioCalamar, Figueres/Berlin Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

This book is dedicated to all patients: you are the force that drives our work and our most important teachers. Thank you. I would like to dedicate this book to all those who are important to me.

 

Foreword I

In the United States, cancer is the second most common cause of death. Over 560,000 people die of cancer each year. One in four deaths in the United States is due to cancer. Since the 1970s, the 5-year survival from cancer has increased from 50% to 66%. This improvement in survival reflects earlier diagnosis and more effective therapies and management strategies. As medical technology improves, even more progress is anticipated, but such progress requires experience and analysis, which only highly experienced clinicians and scientists can amass. Patients with hematologic malignancies are a special challenge to health care providers. In the United States, over 130,000 persons are diagnosed with a hematologic malignancy each year, and over 50,000 individuals die. Half of these hematologic malignancies are acute or chronic leukemias, and the remainder is primarily lymphomas or multiple myeloma. These hematologic malignancies represent 9.5% of the cancer burden in the United States. These patients undergo a wide variety of immunosuppressive therapies that can have impressive results in terms of disease-free survival. However, the toxicities of these regimens can be substantial. Both disease and therapy can cause complications. These complications are very different for different cancers and for different therapies. Our ability to improve the outcome of hematologic malignancies is due to more precise methods to identify the specific malignant process and to an expanding array of treatments for the underlying malignancies. These treatments are often used in combination regimens over periods of many months to years. These treatments include ionizing radiation, cytotoxic drugs, immunosuppressive agents, and stem cell transplantation. There are now over 50 drugs approved in the United States to treat hematologic malignancies. These drugs have an expanding number of mechanisms of action, ranging from traditional cytotoxic agents to newer drugs that are enzyme inhibitors, monoclonal antibodies, or proteasome inhibitors. Each of these approaches offers promise for specific indications, but also produces enormous complexity in terms of the effects on host immune and inflammatory response, and in terms of the specific organ toxicities they produce. In this book, Pulmonary Involvement in Patients with Hematological Malignancies, Élie Azoulay has assembled experienced clinicians from around the world to focus on the infectious and non-infectious pulmonary complications that occur in these patients as they are managed with these diverse therapeutic modalities. Dr. Azoulay is renowned for his experience in dealing with such complications and for his careful investigations, which have improved patient care around the world. He has assembled



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Foreword I

well-published authorities to provide a comprehensive body of information on epidemiology, natural history, diagnosis, and therapy of pulmonary complications. What makes this book especially useful is the focus on very specific clinical scenarios. Clinicians who care for patients with hematologic malignancies, which includes most oncologists, infectious disease specialists, and pulmonary-critical care physicians, will immediately be drawn to chapters on long-standing clinical controversies such as the role for various types of lung biopsies, new molecular techniques to enhance diagnostic accuracy, and chapters on specific pathogens such as Candida, Aspergillus, and CMV. Also of special note are chapters that focus on non-infectious challenges such as diffuse alveolar hemorrhage and transfusion-related lung injury. Dr. Azoulay has also included chapters on management problems, such as invasive and non-invasive ventilation, transfusion policies, and palliative care, which clinicians will benefit from reviewing in order to be certain they are providing state-of-the-art care. This book represents the work of experienced, thoughtful, evidence-based clinicians who provide the authoritative information that only a highly specialized, focused book such as this can supply. Health care providers who deal with this patient population will find the information and insights in this volume to be extremely valuable and will refer to this book often! H. Masur

Foreword II

The number of immunocompromised patients has increased over the last decade. Improvements in solid-organ and hematopoietic stem cell transplantation techniques, the expanded use of chemotherapy and steroid use, and the appearance of immunomodulatory therapies are some of the reasons that explain this increase. The success of the different transplant techniques has generated a great deal of interest in the management of immunocompromised patients among clinicians and basic scientists. The recognition and management of pulmonary complications that result from immunosuppression are challenging tasks. The lungs may be injured directly through infectious or toxic insults. Conversely, lung disease may result as a secondary event. Pulmonary complications in these patients require a multidisciplinary approach that often involves different specialties. This includes an appreciation of the epidemiology of post-transplant pulmonary complications, the different diagnoses for these processes, the appropriate diagnostic explorations, and the specific treatments and potential interactions. Some of these patients with pulmonary complications may need intensive care treatment. The first part of this book is dedicated to non-infectious complications. Dr. Bekele Afessa describes the epidemiology, diagnosis, and treatment of diffuse alveolar hemorrhage, which is a frequent entity in hematological patients. Dr. Afessa provides a very comprehensive review of non-infectious pulmonary involvement after hematopoietic stem cell or bone marrow transplantation. The non-infectious complications comprise a series of entities that may respond to steroid treatment, although in some cases, they will lead to fatal outcomes (graft-versus-host disease). Pulmonary veno-occlusive disease following hematopoietic stem cell transplantation is a rare complication that is difficult to manage. This subject is reviewed in depth by Drs. Bunte and Burns. Not infrequently, drugs used to treat cancer patients have cardiovascular complications. One chapter describes how frequently these complications occur, which drugs may be responsible, and how we can decrease the severity of cardiovascular toxicity caused by these drugs. Diagnosis of pulmonary infiltrates in hematologic malignancies is a difficult problem that often requires bronchoscopic evaluation. Post-mortem studies have helped us to provide the operative values of the techniques that we use in vivo. Dr. Pastores and colleagues have written a comprehensive chapter on this subject. Hematologic malignancies often require transfusions that may be followed by acute lung injury, especially in children. Respiratory infections in patients with hematologic malignancies, neutropenia, and bone marrow transplants continue to be a



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serious problem triggered by abnormalities in the function and number of neutrophils, T and B lymphocytes, anatomic considerations, or a combination of factors. They range from bacterial pneumonias to opportunistic infections. Dr. Soubani et al. provide an update on the etiology, epidemiology, diagnosis, and management of these infections. In summary, this book edited by Dr. Élie Azoulay gathers a series of excellent chapters written by experts in different problems that cause acute lung injury in hematological patients. The book will be very useful for specialists dealing with these types of problems, and this obviously includes intensive care physicians. Prof. Antoni Torres

Acknowledgments

I am grateful to all the authors and co-authors who contributed to this book, spending their valuable time to write thoughtful presentations of difficult topics based on their own clinical experience acquired over the years and on a thorough knowledge of the most recent literature. Many thanks to all of you. I have the deepest respect and consideration for the team working at the medical ICU at the Saint-Louis Hospital. Along with Benoit Schlemmer, I know how lucky we are to work with this group of people who care deeply about their patients and about communicating their skills to their young colleagues. They gladly accept the challenges raised by the sickest patients, while making every effort to avoid nonbeneficial care. I learn everyday from them. I am indebted to the hematologists who work closely with our medical ICU at the Saint Louis Hospital. We learn a lot from each other as we combine our energies to devise the best means of caring for our patients. Our close collaboration has nourished important research projects, shedding new light on topics such as the mechanisms underlying specific organ dysfunctions, emerging infections, and unexpected drug-related toxicities. This new understanding has helped us to improve patient outcomes. I am grateful to Dr Francois Vincent for his critical revision of contributions to this book and his willingness to check every single reference. The huge amount of work he put into this book was invaluable. I owe a debt of gratitude to Meike Stoeck from Springer for her assistance and willingness to adjust to my own pace, as well as to Ute Heilmann for her trust and kindness. I have a personal thought for Dr Arnaud de Lassence who would certainly have written a contribution for this book. He was among those who knew the most about pulmonary involvement in patients with hematological malignancies. The memory of his bright mind and sparkling enthusiasm continues to nourish my work.



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Contents

Part I  Preamble and Introduction   1 Managing Patients with Hematological Malignancies for 25 Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Benoit Schlemmer

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  2 Pulmonary Involvement in Patients with Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Élie Azoulay

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  3 Respiratory Infections in Patients with Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ayman O. Soubani

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Part II  Epidemiology



  4 Epidemiology of Respiratory Events in Patients with HM (Not Including ICU) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Georg Maschmeyer

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  5 Epidemiology of Acute Respiratory Failure in Patients with HM (ICU Only) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carlos Agustí, Carmen Lucena, and Antoni Torres

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  6 Noninfectious Lung Involvement in Patients with Hematological Malignancies (Excluding BMT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bernard Maitre

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  7 Noninfectious Pulmonary Involvement in Hematopoietic Stem Cell or Bone Marrow Transplant Recipients . . . . . . . . . . . . . . . . . Bekele Afessa

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  8 Are There Any Pulmonary Issues Specifically Related to Cord Blood Transplants? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jonathan Gutman

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  9 Cardiovascular Complications of Cancer Therapeutics . . . . . . . . . . . . . Aarif Y. Khakoo and Callie S. Kwartler

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10 Prophylaxis: Peace of Mind? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 Benoit Guery and Karine Faure Part III  Diagnostic Strategy in HM Patients 11 How Type of Malignancy and Treatment Assist in the Etiological Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 Alexandre Boyer and Didier Gruson 12 Contribution of Radiology in Patients with Hematological Malignancies and Pulmonary Involvement . . . . . . . . . . . . . . . . . . . . . . . 131 Claus Peter Heussel 13 Is There Still a Place for Transbronchial Lung Biopsy or Other Lung Biopsy Techniques? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 Christophe Dooms and Vincent Ninane 14 The Increasing Role for Core Needle Biopsy of Pulmonary Lesions in Immunocompromised Patients . . . . . . . . . . . . . . . . . . . . . . . . 155 Cédric de Bazelaire, Raphael Calmon, Marion Chapelier, Amélie Pluvinage, and Eric de Kerviler 15 Minimally Invasive Diagnostic Strategy in Immunocompromised Patients with Pulmonary Infiltrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 Laurent Camous, Virginie Lemiale, Achille Kouatchet, David Schnell, Sandra de Miranda, and Élie Azoulay 16 Pleural Effusions and Thoracentesis in Patients with Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 Michael G. Alexandrakis, Paschalis Steiropoulos, and Demosthenes Bouros 17 Diagnostic Yield of BAL Fluid Cytology in Hematologic Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 Jean-François Bernaudin and Jocelyne Fleury-Feith 18 New Methods for Bacterial Diagnosis in Patients with Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 Agnès Ferroni and Jean-Ralph Zahar 19 FDG-PET Imaging in Haematological Patients with Pulmonary Infiltrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 Tomohiko Yamane

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20 What Has Been Learned from Postmortem Studies? . . . . . . . . . . . . . . . 243 Stephen M. Pastores, Alina O. Dulu, and Shilpa A. DeSouza Part IV  Lung Infections in Patients with HM 21 Common Viral Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257 David Schnell, Jérôme Legoff, and Élie Azoulay 22 Emerging Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 Oliver Schildgen 23 Cytomegalovirus Pneumonia in Patients with Hematologic Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 Karen J. Vigil and Roy F. Chemaly 24 Herpes Simplex Virus Pneumonia in Patients with Hematologic Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 Jharna N. Shah and Roy F. Chemaly 25 Pneumocystis Pneumonia in Non-AIDS Immunocompromised Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 Élie Azoulay, Virginie Lemiale, Achille Kouatchet, François Vincent, Antoine Roux, Guillaume Bollée, and Patricia Roux 26 Diagnosis of Invasive Pulmonary Aspergillosis in Patients with Hematologic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 Marie-Elisabeth Bougnoux, Fanny Lanternier, Emilie Catherinot, Felipe Suarez, and Olivier Lortholary 27 Emerging Fungal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337 Marcia Garnica and Marcio Nucci 28 Candida Pneumonia in Patients with Hematological Neoplasia . . . . . . . 349 Carlos Carvajal, Jordi Rello, and Jeffrey Lipman 29 Parasitic Lung Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357 Jean-François Timsit, Jean-Paul Brion, and Hervé Pelloux 30 Pulmonary Mycobacterial Infections in Patients with Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369 Khalid A. Al-Anazi and Asma M. Al-Jasser Part V  Noninfectious Pulmonary Involvement in Patients with HM 31 Pleuropulmonary Changes Induced by Drugs in Patients with Hematologic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387 Philippe Camus

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32 Cardiovascular Complications of Cancer and Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425 Callie S. Kwartler and Aarif Y. Khakoo 33 Diffuse Alveolar Hemorrhage in Hematopoietic Stem Cell Transplant Recipients and Patients with Hematologic Malignancy . . . . . 437 Bekele Afessa 34 Venous Thromboembolism in Patients with Hematologic Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449 Tarek Sousou and Alok A. Khorana 35 Transfusion-Related Acute Lung Injury in Children with Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461 Rachel S. Bercovitz, J. Bradley Ball, Marguerite R. Kelher, and Christopher C. Silliman 36 Acute Respiratory Distress Syndrome (ARDS) in Neutropenic Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477 Mokart Djamel, Textoris Julien, Ettori Florence, Bruno Chetaille, and Blache Jean-Louis 37 Pulmonary Venoocclusive Disease Following Hematopoietic Stem Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491 Matthew C. Bunte and Linda J. Burns 38 Radiation Pneumonitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499 Miguel Gallego Díaz and Jordi Rello Condomines 39 Leukostasis, Infiltration and Pulmonary Lysis Syndrome Are the Three Patterns of Leukemic Pulmonary Infiltrates . . . . . . . . . . 509 François Vincent 40 Pulmonary MALT Lymphoma: Clinical, Molecular and Therapeutic Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521 Marie Wislez, Raphael Borie, Catherine Thieblemont, Marie-France Carette, Martine Antoine, and Jacques Cadranel 41 ARDS During Neutropenia Recovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533 Élie Azoulay, Eric Ezingeard, Choupi-Salomon Berckowski, and Michael Darmon 42 Fibrosing Alveolitis in Hematologic Malignancy Patients Undergoing Hematopoietic Cell Transplantation . . . . . . . . . . . . . . . . . . 537 Huda Salman, Kenneth R. Cooke, and Hillard M. Lazarus

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Part VI Treatment and Difficult Decisions in Patients with HM and ARF 43 Antibiotic Therapy in Neutropenic Patients . . . . . . . . . . . . . . . . . . . . . . . 553 Matthieu Legrand, Adeline Max, and Bertrand Gachot 44 Antifungal Therapy in Patients with Hematological Malignancies . . . . 569 Raoul Herbrecht and Yasmine Nivoix 45 Antiviral Agents in Patients with Hematological Malignancies and Acute Respiratory Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589 Michael Sandherr 46 Mechanical Ventilation in Patients with Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597 Márcio Soares, Jorge I.F. Salluh, and Pieter O. Depuydt 47 Optimizing Noninvasive Ventilation in Hematological Patients with Acute Respiratory Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607 Gilles Hilbert 48 Noninvasive Ventilation to Ensure the Safety of Fiberoptic Bronchoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617 Massimo Antonelli, Giuseppe Bello, and Riccardo Maviglia 49 NIV Outside the ICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623 Stefano Nava and Sebastiano Mercadante 50 Palliative Noninvasive Mechanical Ventilation in Patients with Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631 Anne-Pascale Meert, Thierry Berghmans, and Jean-Paul Sculier 51 Acute Kidney Injury in Cancer Patients . . . . . . . . . . . . . . . . . . . . . . . . . 637 Michael Darmon, Laurent Camous, Camille Devanlay, Emmanuel Canet, Benoit Schlemmer, and Fabrice Zeni 52 Septic Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651 David Grimaldi and Frédéric Pène 53 Prognostic Factors for Mortality in the Critically Ill Cancer Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665 Kathleen N.S. Cathcart and Jeffrey S. Groeger 54 Managing Critically Ill Cancer Patients: Another Medical Success Story . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671 Élie Azoulay, Marcio Soares, Michael Darmon, Dominique Benoit, Stephen Pastores, and Bekele Afessa

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55 Palliative Care and Dyspnea Management in Patients with Hematological Malignancies and Acute Respiratory Failure . . . . 683 Amy P. Abernethy, Jane L. Wheeler, and David C. Currow 56 End-of-Life Decisions in Cancer Patients . . . . . . . . . . . . . . . . . . . . . . . . . 693 Lieve Van den Block, Agnes van der Heide, and Luc Deliens Part VII  Pearls That You Should be Aware Of 57 An Unexpected Diagnosis of Pulmonary Tuberculosis . . . . . . . . . . . . . . 703 Virginie Lemiale, A. Seguin, and Élie Azoulay 58 Respiratory Symptoms Occurring 4 Months After Allogeneic Hematopoietic Stem Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . 707 Anne Bergeron, Séverine Feuillet, Véronique Meignin, Patricia Ribaud, and Abdellatif Tazi 59 Pulmonary Complications of Chronic Lymphocytic Leukemia . . . . . . . 715 Melhem Solh and Punit Wadhwa 60 Clinical Pearls: Pulmonary Veno-occlusive Disease . . . . . . . . . . . . . . . . 725 Jonathan Gutman 61 Cytarabine-Induced Pulmonary Toxicity in Leukemic Patients . . . . . . 729 Fabio Forghieri, Leonardo Potenza, Monica Morselli, Monica Maccaferri, Giuseppe Torelli, and Mario Luppi 62 Histoplasmosis in a Patient with Chronic Myelogenous Leukemia . . . . 735 Vincent Peigne, Benoît Schlemmer, and Olivier Lortholary 63 Pulmonary Toxicity of Imatinib and Other BCR-ABL Tyrosine Kinase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741 François Vincent 64 Rituximab-Related Pulmonary Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . 751 Yair Herishanu, Chava Perry, and Aaron Polliack 65 Cardiogenic Causes of Respiratory Failure in Patients with Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759 Julien Maizel, Berengere Gruson, Jean-Pierre Marolleau, and Michel Slama 66 Pulmonary Alveolar Proteinosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 771 François Vincent, H. Tandjaoui, and P.Y. Brillet

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67 Pneumocystis jiroveci Pneumonia in a Patient with Diffuse Large B-Cell Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 781 Hung Chang and Lee-Yung Shih 68 Pulmonary Infiltration in Anaplastic T-Cell Lymphoma . . . . . . . . . . . . 787 Christophe Cracco, Julien Mayaux, Sylvain Choquet, Catherine Beigelman, and Frédéric Charlotte 69 A Rapidly Reversible Cause of Pulmonary Embolism . . . . . . . . . . . . . . 793 Sophie Georgin-Lavialle, Élie Azoulay, Fabrice Zeni, and Michael Darmon 70 Hairy Cell Leukemia with Pulmonary Infiltrates . . . . . . . . . . . . . . . . . . 797 Virginie Lemiale, Véronique Meignin, and Élie Azoulay 71 Trichosporon asahii Infection in a Neutropenic Patient . . . . . . . . . . . . . 801 Djamel Mokart, Antoine Sannini, Jean-Paul Brun, Laurent Chow-chine, and Jean-Louis Blache Part VIII  Post Face 72 Who Is This Book for? Reserved to Highly Specialized Teams? . . . . . . 807 Laurent Brochard 73 Pulmonary Involvement in Patients with Hematological Malignancies: And Now? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 809 Patricia Ribaud and Gérard Socié Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 811

 

Part Preamble and Introduction

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Managing Patients with Hematological Malignancies for 25 Years Benoit Schlemmer

Contents References............................................................................

B. Schlemmer  Department of Intensive Care Medicine, Saint-Louis Hospital, Paris, France and University Paris-Diderot, Paris, France e-mail: [email protected]

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In 1986, just 25 years ago, three reports were published by Laufe [1], Maunder [2] and Ognibene [3], focusing on the occurrence of Adult Respiratory Distress Syndrome in neutropenic patients. Hematological patients had just begun to be included in the field of diffuse alveolar damage and pulmonary critical care medicine. For many years, hematological patients were known to experience severe life-threatening conditions because of the course of their underlying disease or complications of therapy. Most of the latter were considered from infectious origin, resulting in sepsis, multiple organ failure and death. Doctors in the field of hematology or cancer were reluctant to admit such patients to the ICU, which was presumed to be futile because of poor results. Most intensivists agreed that this kind of patient was beyond any supportive care. Misknowledge about pathophysiology, concepts, diagnosis and therapy was equally distributed on both sides, in hematology and critical care. The flaws and fears were similar among these physicians. Progress in the field of critical care and respiratory medicine along with therapeutic advances in the field of cancer has progressively changed medical attitudes regarding patients’ medical presentations and the management of hematological patients with pulmonary disease. Medical teams in specialized centers have moved from “just say no” [4] to “consider saying yes” or “let’s perform a trial” [5]. Twenty-five years have been necessary to distinguish among multiple complex medical entities, to increase our knowledge regarding both hematological diseases and complications of therapy. The role of the malignant process and its specific impact on organs and functions, or complex side effects of therapy, such as endothelial damage related to antineoplastic drugs or immune consequences of transplantation, have been

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_1, © Springer-Verlag Berlin Heidelberg 2011

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recognized. In addition, great progress has been made in the field of therapy, resulting in new opportunities and hopes for many patients previously considered to have rapidly fatal diseases. In addition, better knowledge about critical care conditions and the impact of their management by intensivists has also resulted in new concepts and strategies. Where critical care physicians cooperate with their colleagues in hematological wards, they have developed new strategies regarding diagnosis and therapy. The respective benefits of invasive versus noninvasive diagnostic procedures have been discussed, along with the opportunity to use new diagnostic tools in the field of infection or lung injury, from inflammation to healing and fibrosis. Improvement in respiratory therapy, with the development of noninvasive ventilatory support and low tidal volume mechanical ventilation, has resulted in the opportunity to develop the concept of early management for many hematological patients with pulmonary disease before the occurrence of critical conditions, out of the scope of any hope. Medical benefit for patients has been the result of improvement in basic science, pathophysiology and nosology in pulmonary medicine and hematology. Accordingly, better knowledge, better diagnosis and therapeutic advances should result in better strategies and improved patient outcomes. Widening the field of  diagnostic and therapeutic tools in pulmonary medicine for hematological patients has highlighted the need for accurate medical decision-making, both from technical and ethical points of view. When faced with a patient with a history of hematological disease and pulmonary signs, one should now distinguish between several etiologies, choose a diagnostic strategy or empiric therapy, and discuss whether an invasive diagnostic procedure or ventilatory support would be valuable, taking into account probabilities, hope of reversibility, patient willingness and riskbenefit analysis. Intensive care therapy of hematological patients now has to be considered as a way to support critical conditions in order to allow diagnostic procedures and/or therapy to reverse such medical situations. Emergency decisions sometimes have to be made, including in non-specialized medical facilities, because of the great developments in ambulatory medicine for some hematological disorders. However, sometimes, withholding or withdrawal of some therapeutic options has to be discussed, as for

B. Schlemmer

many other patients in ICUs. The medical decision has to be based both on evidence, whenever possible, and experience. Better knowledge in the field of pulmonary involvement in hematological malignant diseases has pushed intensivists and physicians in hematology to share their experience and to provide new opportunities for their patients. This has also resulted in the need for additional research in this field, not only related to acute conditions and their management, but also to long-term outcomes and quality of life. This book will offer any intensivist, even non-specialized, and any physician in the field of hematology and cancer the opportunity to review 25 years of medical progress. Increasing medical knowledge would not only result in answers for hematological patients with pulmonary disease, but would also result in more comprehensive understanding, in new questions for the future and in the opening of new fields for medical research in which both intensivists and cancer physicians should cooperate. In this respect, this book is exemplary. I want to thank all the contributors who have accepted the task of summarizing their outstanding experience for young physicians who need to be educated in the field of such difficult medical conditions. I want to congratulate my young colleague and friend, Elie Azoulay, who is a masterpiece in clinical training and supervision at Saint-Louis Hospital, but also a leader in clinical research, for initiating this huge work and succeeding in the challenge of gathering the most influent specialists in this field of medical care.

References   1. Laufe MD, Simon RH, Flint A, Keller JB (1986) Adult respiratory distress syndrome in neutropenic patients. Am J Med 80:1022–1026   2. Maunder RJ, Hackman RC, Riff E et al (1986) Occurrence of the adult respiratory distress syndrome in neutropenic patients. Am Rev Respir Dis 133:313–316   3. Ognibene FP, Martin SE, Parker MM et  al (1986) Adult respiratory distress syndrome in patients with severe neutropenia. N Engl J Med 315:547–551   4. Carlon GC (1989) Just say no. Crit Care Med 17(1):106–107   5. Lecuyer L, Chevret S, Thiery G, Darmon M, Schlemmer B, Azoulay E (2007) The ICU trial: a new admission policy for cancer patients requiring mechanical ventilation. Crit Care Med 35(3):808–814

 

2

Pulmonary Involvement in Patients with Hematological Malignancies Élie Azoulay

Acute pulmonary events are among the most common complications in patients with hematological malignancies. These events often raise difficult diagnostic and therapeutic challenges. In this book, readers faced with these challenges will find a vast array of clinically relevant information contributed by physicians in many specialties who have acquired considerable experience over the years. Pulmonary complications in patients with hematological malignancies may be related to many factors, including infection, tissue invasion by the malignant cells, toxicity and immune deficiency related to the disease or treatments. The multiplicity of the possible etiologies and frequent presence of more than one etiology in a given patient create diagnostic conundrums. Importantly, an early accurate diagnosis is crucial to improve patient outcomes. This book provides practical guidance on untangling complex diagnoses and selecting optimal treatments. In addition to hematologists, intensivists, and pulmonologists, clinicians from many specialties may be called on to manage respiratory events in patients with hematological malignancies. This book was written to serve as an easily accessible source of information to primary-care physicians, emergencyroom physicians, intensivists and physicians working in internal medicine, infectious diseases or pulmonary care departments. Furthermore, the problems encountered in patients with hematological malignancies are relevant to all specialties where patients

É. Azoulay  Service de Réanimation Médicale, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010, Paris, France and Medical Intensive Care Units, Saint-Louis Hospital, Paris 7 University, Paris, France e-mail: [email protected]

require immunosuppressant treatments for systemic inflammatory diseases, including clinical immunology, rheumatology, hepatology, gastroenterology, nephrology, dermatology, neurology, and solid organ transplantation. This book has six parts. After an introduction by Dr Soubani, who presents a comprehensive overview of infectious etiologies of respiratory events in patients with hematological malignancies, the first part focuses on epidemiology. International leaders draw attention to important points such as the specificities of bone marrow transplant recipients and the possibility of non-infectious pulmonary involvement, most notably heart failure with pulmonary edema whose diagnostic and therapeutic management differ fundamentally from those of other etiologies of respiratory events in hematological patients. The second part addresses ongoing controversies about the best diagnostic strategies, which are largely fueled by the fast pace at which new diagnostic tools are being introduced. Renowned researchers discuss the latest information on the benefit/risk ratio of diagnostic tools ranging from the least invasive (clinical examination) to the most invasive (surgical lung biopsy). This careful attention to diagnostic tools is warranted, as mortality is higher when no cause to the respiratory symptoms is identified. In patients who are not receiving mechanical ventilation, noninvasive diagnostic testing may provide comparable diagnostic yields to those obtained using bronchoscopy with bronchoalveolar lavage. Attention is drawn to the valuable information that can be derived by the optimal use and interpretation of lung computed tomography. In the third and the fourth parts of this book, leading researchers describe the spectrum of pulmonary infections in hematological patients because of pathogens ranging from common bacteria to opportunistic pathogens, and the spectrum of

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_2, © Springer-Verlag Berlin Heidelberg 2011

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noninfectious causes, including drug-related toxicity, pulmonary embolism, diffuse alveolar hemorrhage, and alveolar proteinosis. The fifth part provides new insights into treatments and difficult decisions for patients with hematological malignancies. Contri­ butions from physicians in various specialties were assembled to shed light on the many facets of this topic. Opinion leaders provide recommendations on the use (or withdrawal) of various therapeutic strategies. Last, the sixth part presents 15 carefully selected case reports about clinical situations that are rare but important. The goal is to improve the diagnosis of rare but treatable conditions. For each clinical situation, a literature review is reported. These case reports may constitute valuable teaching material for discussing patients with unusual problems. The abundance of tables, figures, radiographs, and computed tomography scans in the book considerably enriches the written material. Three methods can be suggested for using this book. First, you can look up a clinical situation you are interested in (e.g., pneumonia in patients with chronic lymphocytic leukemia or pulmonary infiltrates at the earliest phase of acute leukemia). Second, you can look for the diagnostic strategy that is best for evaluating a clinical suspicion of infectious or noninfectious pulmonary involvement (e.g., induced sputum, transbronchial biopsy, or core needle biopsy). Third, you can find a description of the clinical picture related to a given form of pulmonary involvement or a given pathogen (e.g., Pneumocystis pneumonia, cytomegalovirus pneumonia, cardiogenic pulmonary edema, diffuse alveolar hemorrhage, or transfusion-related acute lung injury). These three methods can complement one another. Therapeutic alternatives are also available for all these situations. I hope this book will spread ten important messages. First, in patients with hematological malignancies who experience respiratory complications, treating every possible etiology is not the best way to ensure a favorable outcome. Instead, identifying the exact cause improves survival. Second, within the first few hours the most likely causes of the respiratory symptoms should be determined based on the clinical findings (see the DIRECT strategy) and recorded in the medical chart. Treatments appropriate for these causes should be given immediately, while waiting for the results of further investigations. Third, computed tomography may help to support a clinical suspicion

É. Azoulay

of an infectious or noninfectious cause and may also rule out a number of etiologies. However, computed tomography alone cannot establish a diagnosis. Furthermore, computed tomography should be performed only after a comprehensive clinical assessment, whose findings guide the choice of the imaging strategy. Fourth, not all patients are at risk for all the possible etiologies. Knowledge of the specific risk factors for each cause is crucial. For instance, the type of immune deficiency indicates which pathogens are most likely to cause pulmonary involvement. A discerning risk factor assessment may show that some patients are at very low risk for some causes. Fifth, two diagnoses, cardiogenic pulmonary edema and bacterial infections, should be considered in all patients at all times during the course of the hematological malignancy. Sixth, positive tests (e.g., cytomegalovirus antigen test, PCR test for Pneumocystis, or virological studies of nasopharyngeal swabs) must be interpreted with great caution. A positive test does not always mean that the disease is present. Furthermore, several causes may be present in combination. For instance, even when the bronchoalveolar lavage fluid indicates alveolar hemorrhage, infections (e.g., aspergillosis, Pseudomonas, Staphylococcus, and other causes of necrotizing pneumonia), and noninfectious disorders (e.g., cardiogenic pulmonary edema, leukemic infiltrates, and drug-related toxicity) must be ruled out before accepting a diagnosis of diffuse alveolar hemorrhage and initiating the specific treatment for this condition. Another important point is that negative results do not always exclude diagnoses, such as cytomegalovirus pneumonia, Pneumocystis pneumonia, or invasive aspergillosis. The few diagnostic tests whose negative predictive value is close to 100% (e.g., PCR test for Pneumocystis) are extremely valuable. Seventh, thrombocytopenia does not protect against the occurrence of thromboembolic events. Eighth, core needle biopsy performed by an experienced operator can provide valuable diagnostic information. As with all invasive procedures, the ICU may be the safest place to monitor the patients before and after core needle biopsy. Ninth, each new diagnostic method must be carefully evaluated in a group of unselected patients with hematological malignancies. The diagnostic performance characteristics must be reported, together with the prevalence of the disease in the study group. Tenth, managing patients with pulmonary events and

2  Pulmonary Involvement in Patients with Hematological Malignancies

hematological malignancies requires considerable clinical skill, close collaboration among medical specialties and with the laboratories, and easy access to the ICU. Among patients with hematological malignancies, more than half experience critical illnesses, and early ICU admission may be the best means of

7

providing them with optimal diagnostic and therapeutic care. I owe an enormous debt of gratitude to the specialists who provided their valuable contributions to this book. Élie Azoulay

 

3

Respiratory Infections in Patients with Hematological Malignancies Ayman O. Soubani

Contents 3.1 Introduction.............................................................

3.1 Introduction 9

3.2 The Immune System Changes in Patients with Hematological Malignancies......................... 10 3.3 Bacterial Pneumonia.............................................. 13 3.4 Fungal Infections.................................................... 17 3.4.1 Aspergillus................................................................ 17 3.4.2 Other Fungi............................................................... 23 3.5 Cytomegalovirus..................................................... 25 3.6 Community Respiratory Viruses........................... 3.6.1 Respiratory Syncytial Virus (RSV).......................... 3.6.2 Parainfluenza Virus................................................... 3.6.3 Influenza................................................................... 3.6.4 Adenovirus................................................................ 3.6.5 Other Viruses............................................................

27 28 29 29 29 29

3.7 Conclusion............................................................... 30 References............................................................................ 30

A.O. Soubani  Associate Professor of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine Wayne State University School of Medicine, Harper University Hospital, 3990 John R-3 Hudson, Deotrit, MI 48201 e-mail: [email protected]

Hematological malignancies are a variety of cancers that involve the hematopoietic cell lines. They include acute and chronic leukemias, Hodgkin’s disease, non-Hodgkin’s lymphomas, multiple myeloma and myelodysplastic syndrome. The age-adjusted incidences of leukemias and lymphomas in the United States are 12.2 and 22.3 per 100,000 population per year, respectively. While the age adjusted death rate for leukemias is 7.3 and for lymphomas is 7.5 per 100,000 population per year [1]. Bone marrow and hematopoietic stem cell transplantations (HSCT) are an important treatment for a variety of hematological malignancies as well as other diseases such as hematological disorders, solid tumors and autoimmune diseases. Annually, there are more than 30,000 cases of autologous HSCT and 15,000 cases of allogeneic HSCT performed worldwide [2]. Hematopoietic stem cells may be obtained from bone marrow, peripheral blood or umbilical cord blood. Depending on the source of these stem cells, HSCT is classified as autologous if the cells are taken from an individual patient and stored for reinfusion after high-dose chemotherapy, and it is classified as allogeneic if the stem cells are donated from another individual (who may or may not be related). In the case of allogeneic HSCT, the conditioning regimen before transplantation may be myeloablative, in which supralethal doses of chemotherapy and irradiation are given, leading to significant toxicity and immunosuppression. More recently, nonmyeloablative regimens have been used to minimize the toxicity related to the conditioning regimen and allow for more robust immunologically mediated killing of tumor cells (graft vs. tumor effect).

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_3, © Springer-Verlag Berlin Heidelberg 2011

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Pulmonary complications, both infectious and noninfectious, are important causes of morbidity and mortality in patients with hematological malignancies (Table  3.1). The incidence of these complications reaches 60% of patients [3, 4]. Mortality of pulmonary complications is 40% and approaches 90% in patients who require mechanical ventilation [5]. The pulmonary complications are generally related to the underlying malignancy or toxicity of the chemotherapeutic regimen. In the case of HSCT, there are additional complications related to graft-vs.-host disease (GVHD), which is a condition in which the donated cells recognize the recipient’s cells as nonself and attack them. Efforts to prevent or treat GVHD include harvesting hemato­ poietic stem cells from an HLA-matched donor and use of immunosuppressive and immunomodulatroy the­ rapy such as corticosteroids, cyclosporine or tacrolimus

Table 3.1  Spectrum of respiratory infectious and noninfectious complications in patients with hematological malignancies Infectious   Bacteria   Mycobacteria   Nocardia   Aspergillus

A.O. Soubani

(FK506) or TNF-a blocking agents [6]. The use of these agents entails further hazards for infectious complications and the development of a new neoplastic disease. The etiology of pulmonary disease following hematological malignancies may be predicted based on variables such as the type of immunodeficiency, the presence of neutropenia, the prophylactic agents the patient is on and the temporal relation to the administration of chemotherapy. The pattern of pulmonary complications is best demonstrated following allogeneic HSCT (Fig. 3.1). This chapter details the spectrum of respiratory infections in patients with hematological malignancy, focusing on HSCT as the prime example of immunosuppression that develops in these patients. The main respiratory infections in patients with hematological malignancies are described along the lines of incidence, risk factors, clinical presentation, and recent advances in the diagnosis and management. The designation of “patients with hematological malignancies” throughout the chapter is used to describe patients who have a malignancy such as leukemia, lymphoma, multiple myeloma or myelodysplastic syndrome; are on chemotherapy; are neutropenic; or underwent HSCT. Data that are unique to one subgroup are specifically mentioned.

  Non-Aspergillus fungi   P. jiroveci   CMV   Community respiratory viruses Non-infectious   Pulmonary edema (cardiogenic and noncardiogenic)   Transfusion-related lung injury   Engraftment syndrome   Diffuse alveolar hemorrhage   Idiopathic pneumonia syndrome   Organizing pneumonia   Drug induced pulmonary toxicity   Radiation pneumonitis   Pulmonary thromboembolic disease   Secondary alveolar proteinosis   Bronchiolitis obliterans   Progression of underlying malignancy

3.2 The Immune System Changes in Patients with Hematological Malignancies The risk of infection in patients with hematological malignancies primarily stems from defects in the number or function of neutrophils, T-cells and B-cells. Abnormalities in each of these cell lines increase the risk of specific infections (Table  3.2). However, the functions of these defense mechanisms are interdependent, so an abnormality in one cell line may compromise the function of other defense mechanisms. Neutropenia is the most frequent immunodeficiency in patients with hematological malignancies. It is seen in patients with acute leukemia and secondary to myelosuppression following chemotherapy. In addition to decreasing the production of neutrophils, cancer chemotherapy and radiation interfere with the chemotactic and phagocytic activity and the intracellular killing

3  Respiratory Infections in Patients with Hematological Malignancies Fig. 3.1  The time line of pulmonary complications following HSCT. HSV herpes simplex virus, HZV herpes zoster virus, CMV cytomegalovirus, RSV respiratory syncytial virus, CHF congestive heart failure, BO bronchiolitis obliterans, VOD veno-occlusive disease, ES engraftment syndrome, DAH diffuse alveolar hemorrhage, BOOP bronchiolitis obliterans organizing pneumonia, IPS idiopathic pneumonia syndrome, PTLPD post transplant lymphoproliferative disorder

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Phase I Pre-engraftment (0–30 days) Host immune system defect

Phase II Phase III Post-engraftment (30– Late Phase 100 days) >100 days)

Neutropenia, mucositis, Impaired cellular immunity catheters and lines, Acute GVHD acute GVHD

Infectioue

Impaired humoral and cellular immunity chronic GVHD

gram - bacteria Gram + bacteria (Staph, Strep)

Encapsulated bacteria

Candida

No cardia

Aspergillus

Aspergillus Pneumocystis HZV

HSV CMV CRV (PIF, RSV, influenza, adenovirus) Non-infectioue

CHF ES

BO

VOD BOOP

DAH IPS

PTLPD

Table 3.2  Spectrum of immunosuppression in patients with hematological malignancies Mechanism of immunosuppression Causes of immunosuppression Spectrum of respiratory infections Neutropenia

Leukemia

Gram-negative bacilli

Myelodysplastic syndrome

Gram-positive cocci

Chemotherapy

Fungi (candida, Aspergillus)

HSCT Neutrophil dysfunction

Lymphoma

Fungi (P. jiroveci, Aspergillus)

Corticosteroids Myelodysplastic Syndrome T-cell defects

Lymphoma

Bacteria (including nocardia, mycobacteria)

Lymphoblastic leukemia Chemotherapy

Viruses (CMV)

Monoclonal antibodies

Fungi (Aspergillus, P. jiroveci)

Corticosteroids

B-cell defects

HSCT

Parasites

Lymphoma

Encapsulated bacteria (S. pneumoniae, H. influenza)

Leukemia Multiple myeloma Splenectomy Monoclonal antibodies Anatomic

Tumor obstruction

Gram-positive cocci

Mucositis

Gram-negative bacilli

Indwelling catheters

Anaerobic bacteria Candida

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of microorganisms by these cells. Furthermore, ­corti­costeroids, used as part of chemotherapeutic regimens, decrease the accumulation of neutrophils at inflammation sites by reducing their adherence and chemotactic properties. The usual infections associated with abnormalities in the number or function of neutrophils are bacteria, including gram-negative bacilli, and opportunistic fungal infections, such as Aspergillus. The risk of infection increases significantly when the absolute neutrophil count falls below 500 cells/mm3. The risk of infection is greatest with neutrophil counts less than 100 cells mm3. The rate of decline in neutrophil count and the duration of neutropenia are also important factors in the risk of infection. Thus, a patient with acute leukemia is at higher risk of infection when the neutrophil count drops rapidly compared to one in whom the counts fall slowly or remain stable. The longer neutropenia lasts, the higher is the risk of infection. Almost all patients with neutrophil counts less than 100 cells mm3 for more than 3 weeks develop fever. Neutropenia that lasts more than 10 days significantly increases the risk of invasive fungal infections. In one study, the risk of Aspergillus infection was increased by 1% each day of neutropenia for the first 3 weeks, then by 4% each day thereafter [7]. B cells differentiate and proliferate to antibody-­ producing plasma cells upon exposure to bacterial antigens. These cells are responsible for the humoral branch of the immune system. They produce different immunoglobulins, such as IgM and IgA, that protect the body against bacteria and viruses. The production of these immunoglobulins is decreased in lymphoproliferative disorders such as chronic lymphocytic leukemia and multiple myeloma, intensive chemotherapy and treatment with monoclonal antibodies such as rituximab. Abnormalities in the B cell number and function predispose to infection with encapsulated bacteria such as Streptococcus pneu­ moniae, Haemophilus influenza and Staphylococcus aureus. T cells are responsible for cellular immunity and play a pivotal role in regulating monocyte-macrophage antigen handling and intracelullar microbial elimination by the release of various cytokines and chemokines. The function of T cells is compromised in patients with malignant lymphomas, especially Hodgkin’s disease, lymphocytic leukemia and T-cell leukemia. Chemotherapeutic agents, such as cyclophosphamide, azathioprime, purine analogues

A.O. Soubani

including fludarabine and cladribine, and imm­ unosuppressive agents inclu­ding corticosteroids, cyclosporine, tacrolimus and sirolimus, suppress the T cell function. Also novel agents used in the management of lypmhoproliferative malignancies, such as monoclonal antibodies anti-CD52 (e.g., alemtuzumab), significantly affect the function of these cells. Abnormalities in T-cell function predispose patients to infections by fungi, including Aspergillus and Pneumocystis jiroveci, viruses, nocardia and mycobacteria. Other factors that compromise the immune system in patients with hematological malignancies and increase the risk of infection include mucositis secondary to chemotherapy that may predispose to aspiration or translocation of microorganisms from the gastro­intestinal tract. Vascular catheters inserted for ­chemotherapy, parenteral nutrition and transfusion of blood products may be a source of bacterial and fungal infections. Splenectomy, which is occasionally performed in the management of patients with mal­ ignant lymphoma, compromises the production of opsonizing antibodies and impairs the defense against encapsulated bacteria. HSCT is the prototype of immunological abnormalities related to hematological malignancies. HSCT recipients develop profound changes in the immune system that affect all lines of defense against infection (Table 3.3). These patients develop neutropenia immediately following transplantation and may have both T- and B-cell problems related to chemotherapy, GVHD and immunosuppressive therapy. The patients typically follow a predictable pattern of immune system deficiency and recovery. During the first month after HSCT, the major host-defense deficits include neutropenia, damaged muc­ocutaneous barriers and indwelling intravenous catheters. The organisms that commonly cause infection during this period include gram-negative bacilli (e.g., Klebsiella, Escherichia and Pseu­domonas), gram-positive cocci (e.g., coagulase-negative and coagulase-positive Staphylococci, Enterococcus), Candida species and herpes simplex virus. Aspergillus spp. may lead to infection if neutropenia persists. During preengraftment, the risks for infection are the same for ­autologous or allogeneic patients, and infection may present as febrile neutropenia. Although fever during this period is probably caused by a bacterial pathogen, an organism or site of infection is infrequently identified. Instead,  such infections are usually treated

3  Respiratory Infections in Patients with Hematological Malignancies Table 3.3  Factors that increase the risk of respiratory infections following HSCT Pre-transplantation   Older age   Pre-transplant immune status   Underlying pulmonary disease   CMV status of the donor and recipient   Residence in endemic areas Transplantation   Allogeneic   Type and intensity of conditioning regimen   Total body irradiation   Delayed engraftment Post-transplantation   Mucositis   Severity and duration of neutropenia   GVHD   T-cell depleting strategies  Nosocomial factors (antibiotic-resistant organisms, indwelling catheters, construction, type of air filtration, transmission of infection by health-care providers)

preemptively or empirically until the neutropenia resolves. Growth factors can be administered to decrease neutropenia duration and complications. The risk of infection persists until the stem cells are engrafted, which is defined as sustained absolute neutrophil count of 500 cells/mm3 and sustained platelet count of >20,000, lasting >3 consecutive days without transfusions. Among unrelated allogeneic recipients, engraftment occurs at a median of 22 days after HSCT (range 6–84 days) [8]. Following engraftment (30–100 days) and in the absence of corticosteroid therapy, neutrophil function is restored, which results in a decreased risk for bacterial and fungal infections. However, all HSCT recipients, and particularly allogeneic recipients, experience an immune system dysfunction for months after engraftment. They may have abnormal CD4/CD8 T-cell ratios, reflecting their decreased CD4 and increased CD8 T-cell counts [6]. They might also have IgG and IgA deficiencies for months after HSCT and have difficulty switching from IgM to IgG production after antigen

13

exposure. Immune system recovery might be delayed further by CMV infection [9]. During this phase, allogeneic HSCT recipients usually develop acute GVHD that manifests as skin, gastrointestinal and liver injury. GVHD is associated with increased risk of infection due to delayed immunologic recovery. Furthermore, the immunosuppressive therapy used for GVHD prophylaxis and therapy puts HSCT recipients at an increased risk for opportunistic viral and fungal infections. The usual infectious agents during this phase include CMV, Aspergillus and P. jiroveci. After 100 days following HSCT, some patients with allogeneic transplantation continue to have manifestations of chronic GVHD. This phase may be associated with cellular and humoral immunodeficiencies, including macrophage deficiency, impaired neutrophil chemotaxis and poor response to vaccination. Also patients may experience long-lasting IgA and IgG deficiencies, poor opsonization and impaired reticuloendothelial function [10, 11]. After chronic GVHD resolves, which might take years, cell-mediated and humoral immunity function are gradually restored. Patients in this phase are at an increased risk for infections caused by encapsulated organisms, such as S. pneumoniae, H. influenzae or Neisseria meningitidis. They may also develop infections as a result of cytomegalovirus (CMV), herpes zoster virus, community respiratory viral infections and Aspergillus.

3.3 Bacterial Pneumonia Bacterial pneumonia caused by gram-positive or gramnegative organisms is a significant problem in patients with hematological malignancies. These bacteria may lead to community- or hospital-acquired pneumonia. They account for 15% of all respiratory infections [12]. Based on surgical lung biopsy, bacterial pneumonia is estimated to be 2%, but increases to more than 25% when documented by autopsy [13]. The mortality associated with bacterial pneumonia in these patients reaches 22% [14]. One of the main challenges in the diagnosis of bacterial pneumonia in patients with hematological malignancies is the inability to identify the organism in the majority of patients, which may underestimate the incidence of these infections. This is related to the contamination of respiratory samples by

14

upper airway organisms, the fact that most of these patients are on prophylactic antibiotics and the limitations in performing invasive procedures such as bronchoscopy to confirm the cause of infection. There is ongoing controversy on the value of these invasive procedures in the diagnosis of bacterial pneumonia in these patients [8]. Factors that generally increase the risk of bacterial pneumonia in patients with hematological malignancies include their immune status, chemotherapeutic regimen, and degree and duration of neutropenia [4, 15]. The presence of GVHD in patients with allogeneic HSCT significantly increases the risk of bacterial pneumonia because of slower reconstitution of the immune system, impairment of the reticuloendothelial system and opsonization. Furthermore, the immunosuppressive therapy to treat GVHD increases the risk of bacterial pneumonia in these patients [15]. Other factors that predispose to bacterial pneumonia include mucositis that increases the risk of aspiration, especially with the use of narcotic analgesics. Indwelling catheters that increase the risk of bacteremia and septic embolization to the lungs (Fig. 3.2) [16]. The presentation of bacterial pneumonia in patients with hematological malignancies may be subtle, and not infrequently patients present with neutropenic fever with no localizing symptoms and signs due to blunted inflammatory response [17]. Radiological signs may also be scarce. The chest radiograph usually shows focal consolidation, however may

Fig. 3.2  CT scan of the chest showing multiple peripheral nodules, some with cavitation, consistent with septic pulmonary emboli in a HSCT recipient with methacillin resistant S aureus bactermia secondary to indwelling central venous catheter

A.O. Soubani

be normal. The infiltrates may progress quickly to multifocal or diffuse changes that are compatible with acute respiratory distress syndrome. High-resolution computerized tomography of the chest is recommended in febrile neutropenic patients, which may show pulmonary infiltrates in up to 50% of patients with negative chest radiographs [18, 19]. A chapter from Heussel in this book details the different CT patterns in hematological patients with pulmonary infiltrates. The main organisms identified as causes of bacterial pneumonia in neutropenic patients and during the pre-engraftment phase of HSCT are usually gram-negative bacteria such as pseudomonas, klebseilla and enterobacter. In a recent report of the utility of bronchoscopy following HSCT, the most commonly isolated bacteria following HSCT was pseudomonas that was resistant to the current antibiotics [8]. There is also increasing incidence of grampositive bacteria, such as S. aureus, Enterococcus faecium and a-hemolytic streptococcus, which may be associated with septic shock and acute respiratory distress syndrome. Anaerobic organisms may be causative agents in the case of aspiration [16, 20, 21]. Following HSCT, patients continue to be at risk for bacterial pneumonia post engraftment of the stem cells, albeit less frequently. The risk factors for bacterial pneumonias during this period are the presence of acute or chronic GVHD and the immunosuppressive therapy used to treat these patients. These patients are at risk of infection with encapsulated organisms such as S. pneumoniae and H. influenza. However, ­gram-negative organisms may be the etiology in up to 25% of patients [12, 14, 15, 22]. In a report of 1,359 HSCT recipients, 25% of the patients developed at least one episode of pneumonia. Bacterial pneumonia was documented in 9% of all patients and was the most common etiology in those in whom an organism was identified. The most frequent isolate was S. pneu­ moniae, and gram-negative organisms were isolated in 23% of those patients. The 1-year survival of patients after bacterial pneumonia was 71% [22]. In another report, S. pneumoniae pneumonia was documented in 0.7% of HSCT recipients. The majority of these patients underwent allogeneic HSCT and had chronic GVHD. Infection was more common in patients with a history of lymphoma and those on high-dose corticosteroid therapy. Pneumococcal vaccine breakthrough developed in 11% of the cases. The infection occurred a mean of 433 ± 669 days post transplan­tation, and 76% of the patients had

3  Respiratory Infections in Patients with Hematological Malignancies

bacteremia. Mortality due to pneumococcal infection was 13%. Admission to the critical care unit and higher APACHE II score were associated with worse outcome [23]. A retrospective report on invasive pseudomonas infection following HSCT revealed the incidence to be 1.65% a median of 63 days post HSCT. Attributable mortality was 36%. The risk factors for poor outcome were the presence of copathogens and highdose corticosteroid therapy. Sixteen percent had recurrence of pseudomonas infection [24]. The clinical and radiological picture is usually classical for bacterial pneumonia. Antibiotic therapy during this period should be based on the organisms suspected or identified. Patients with hematological malignancies are infrequently reported to develop Legionella pneumonia. A recent study of 49 patients found that lymphopenia, the use of systemic corticosteroids and chemotherapy were the most common underlying conditions. Positive DFA was the diagnostic method in 84% of patients. The case fatality rate was 31% [25]. A prolonged course of therapy with macrolide or fluroquinolone may be necessary in the majority of patients. Legionella pneumonia has also been reported following HSCT. Allogeneic HSCT recipients with GVHD seem to be at highest risk for this infection [17, 26]. Empiric broad-spectrum antibiotics should be started immediately when bacterial pneumonia is suspected in patients with hematological malignancies. The American Thoracic Society guidelines for the treatment of health-care associated pneumonia in patients with risk factors such as HSCT or neutropenia recommend a regimen that includes antipseudomonal cephalosporin or carbepenem, or B lactam, plus antipseudomonal fluroquinolone or aminoglycoside, plus linezolid or vancomycin if methicillin-resistant S. aureus is suspected. In patients who develop bacterial pneumonia late following HSCT, coverage of encapsulated organisms with a fluoroquinolone is recommended. The antibiotic regimen should be narrowed if the etiologic agent is identified [27, 28]. The institutional resistance pattern needs to be considered when determining the choice of antibiotics [19]. Further recommendations on the use of anti-bacterial agents in patients with hematological malignancies are provided in the chapter from Legrand et al.

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Prophylactic measures against bacterial pneumonia include intravenous immunoglobulins in allogeneic HSCT recipients with low IgG level (Table 3.4) [29]. Antibiotics with activity against encapsulated organisms are recommended during the treatment of chronic GVHD. However, it should be noted that the routine use of prophylactic fluoroquinolones in the early posttransplant phase may be associated with an increased incidence of infections due to coagulase-negative staphylococci and gram-negative bacilli resistant to fluorquinolones [30]. Nocardia infection has been rarely reported in patients with hematological malignancies with an incidence ranging between 0.3 and 1.7% [31, 32]. In a study of 6,759 HSCT recipients, 22 cases of proven or probable nocardia infection were reported [32]. The infection was diagnosed a median of 210  days following transplantation. The main predisposing factors for developing nocardiosis were neutropenia, active acute or chronic GVHD, and lack of prophylaxis with trimethoprim-sulfamethoxezole (TMPSMZ). In all except one patient, Nocardia asteroides was the causative agent. Pulmonary involvement occurs in 56% of patients, and the most common radiological findings are nodules with or without infiltrates. Cavitary lung lesions and empyema are other common features of nocardia infection (Fig.  3.3). The diagnosis of nocardia pneumonia is usually made by bronchoalveolar lavage (BAL), although occasionally the organism is detected by culture of sputum or tracheal secretions. If these methods are nondiagnostic, then the diagnosis could be confirmed by CT-guided aspirate of a pulmonary nodule or surgical lung biopsy. In 36% of patients there is co-infection with other organisms such as CMV and Aspergillus [32]. Treatment of nocardia infection is by prolonged administration of TMP-SMZ. Second-line agents are available if there are allergy or side effects associated with sulfa preparations. These second-line agents include amikacin, minocycline, cephalosporin or imipenem. Response to treatment is generally good, and long-term survival in patients with nocardiosis is not significantly different from controls [32]. Prophylaxis against P. jiroveci using low-dose TMP-SMZ has an added benefit of reducing the incidence of nocardia infection in high-risk patients. An entire chapter on pulmonary tuberculosis and other mycobacterial infections in patients with

16

A.O. Soubani

Table 3.4  Suggested prophylactic options against respiratory infections in patients with hematological malignancies Infection First choice Alternate choice Comments Bacteria

Fluoroquinolone

Macrolides

Intravenous immunoglobulins only if IgG level <400 mg/dL

9-month therapy Add pyridoxine 25–50 mg daily

Intravenous immunoglobulins Pneumococcal vaccine H. influenza B vaccine Mycobacteria

Isoniazid 300 mg/day

Rifampin

Aspergillus

Posaconazole 200 mg three times daily

Voriconazole Itraconazole Echinocandins

Candida

Fluconazole 400 mg/day orally or IV

Echinocandins

During neutropenia

Voriconazole TMP/SMZ double-strength one tablet/day or three times/week

Dapsone

Prolonged corticosteroids treatment

Aerosolized pentamidine

Allogeneic HSCT: from engraftment for 6 months and during immunosuppressive therapy for GVHD

Gancyclovir 5 mg/kg/dose twice daily for 7–14 days, followed by 5 mg/kg/day for 5 days/week

Foscarnet

Allogeneic HSCT: until day 100 or for a minimum of 3 weeks. Monitor CMV antigen for duration of treatment

RSV

RSV immunoglobulins 750 mg/kg/ month

Aerosolized ribavirin

Influenza

Lifelong annual seasonal Influenza vaccine

Rimantadine

P. jiroveci

CMV

Valgancyclovir

Based on pediatric HSCT during the high season months

Amantadine Oseltamivir

Herpes

Acyclovir 200 mg orally 3 times/ day or 250 mg/m2/dose twice daily intravenously

Valacyclovir

Herpes zoster virus

Herpes zoster immunoglobulin 625 U IM

Acycolvir

hematological malignancies is presented in this book by Dr. Al Anazi and colleagues. Briefly, Myco­ bacterium tuberculosis is rare in patients with hematological malignancies. The incidence of M. tuberculosis in patients with hematological malignancies varies significantly depending on whether the patients lived in an endemic area. In a large cancer center in the United States, the overall rate of active M. tuberculosis infection was 0.2 in 1,000 new cancer diagnoses. Five out of the 18 patients described had hematological malignancies, and 4 were neutropenic [33]. In a report

HSCT: Until engraftment or day 30

Valacycolvir

from India of 130 patients with acute leukemia, 9 cases (6.9%) had active tuberculosis [34]. In HSCT recipients the reported incidence of M tuberculosis ranges from 0.4% to 5.5% [35–40] The prevalence of M. tuberculosis in autologous HSCT is similar to that in the general population, whereas in allogeneic HSCT recipients, M. tuberculosis infection increased by threefold [36]. A recent review of the literature reported the overall frequency of M. tuberculosis infection in HSCT recipients to be 0.4%, with only 2% of infections

3  Respiratory Infections in Patients with Hematological Malignancies

Fig. 3.3  CT scan of the chest showing a wedge shaped infiltrate in the left upper lobe with cavitation in a patient with GVHD on immunosuppressive therapy following HSCT who developed nocardia pneumonia

developing during neutropenia; 23% were during the first 100 days post-transplantation, and 75% were after the first 100  days [40]. In another review of 2,241 patients who underwent HSCT, only 11 patients (0.49%) had mycobacterial infection; 2 patients had M. tuberculosis, 2 M. avium intracellulare and the rest had rapidly growing mycobacteria organisms. All patients responded well to antimycobacterial treatment [35]. The main risk factors for M. tuberculosis in patients with hematological malignancies are allogeneic transplantation, total body irradiation, chronic GVHD, corticosteroid therapy and residence in endemic areas [36–40]. In HSCT recipients the median time for M. tuberculosis infection was 324  days in one study [36]. The clinical and radiological picture of M. tubercu­losis infection in these patients is generally similar to non-immunocom­ promised patients. However, atypical presentations, including rapidly progressive ­disease, lack of cavitation and extrapulmonary manifestations, have been described in patients with hematological malignancies [33, 41]. The diagnosis of M. tuberculosis infection is usually made by smear and culture from sputum, BAL or pleural fluid samples. Rapid diagnosis of M. tuberculosis may be established by PCR test on the above samples. It is important to check the positive samples for drug susceptibility.

17

Treatment of M. tuberculosis infection in patients with hematological malignancies is similar to other patient populations. However, rifampin should be used with caution because of potential interaction with ­commonly used medications in this patient population, such as fluconazole and calcineurin inhibitors [19, 42]. Some studies suggested a full 1 year of treatment [40]. Diagnosis of latent M. tuberculosis may be difficult in patients with hematological malignancies given the degree of immunosuppression. The tuberculin skin test with 5 mm or more induration as well as a history of significant exposure to patients with active M. tubercu­ losis infection may be indications for treatment [19]. Diagnostic yield of T-cell interferon gamma release blood assays is important [43]. Nontuberculous mycobacterial infections (such as M. avium complex, M. kansasii, M. chelonae) are rare in patients with hematological malignancies. In HSCT recipients the incidence has been generally reported to be less than 1% of all patients [44]. However, in one report from Memorial Sloan Kettering Hospital, the incidence of nontuberculous mycobacterial infection was 2.8% of HSCT recipients [45]. This higher incidence was considered to be related to environmental and historical factors. In a review of 93 cases of nontuberculous mycobacterial infection in HSCT recipients reported in the literature, the median time to diagnosis was 4 months following transplantation, and 46% of patients had GVHD. The infection resolved with medical therapy in 62% of patients. The attributed mortality to nontuberculous mycobacteria was 7.5% [44]. Non­tuberculous mycobacteria may colonize the airways of the patients having chronic lung disease, such as bronchiectasis, which may create a challenge in determining the significance of isolating these bacteria from lower respiratory tract samples. In the case of M. avium intracellulare, first-line therapeutic agents include clarithromycin, azithormycin, ethambutol, rifampin and rifabutin for 18 months (12 months after negative cultures) [46, 47].

3.4 Fungal Infections 3.4.1 Aspergillus Aspergillus is a filamentous fungus that is ubiquitous in the environment. The Aspergillus species are present in the environment as small conidia that are

18

regularly inhaled into the lungs. In the lungs, they change into hyphae that are short and septate, with acute angle branching. Alveolar macrophages and peripheral blood neutrophils are the primary defense mechanism against this fungus. T helper cells and their cytokines (such as TNF-a, interferon-g, IL-12 and IL-15) augment the activity of macrophages and neutrophils against Aspergillus. Neutropenia and defects in T-helper cell function in patients with hematological malignancies make these patients especially vulnerable to invasive disease by Aspergillus. A chapter from Bougnoux and colleagues in this book reports an upto-date and comprehensive review on invasive pulmonary aspergillosis in patients with hematological malignancies. Invasive pulmonary aspergillosis (IPA) is the most common invasive fungal infection in patients with hematological malignancies, with a steady rise in the documented cases. Following HSCT, the risk for IPA is much higher following allogeneic HSCT when compared to autologous transplantation (incidence is 0.5–4% in autologous HSCT compared to 2.3–15% in allogeneic HSCT [48–52]). After autologous HSCT, IPA is mainly seen during the neutropenic phase. In allogeneic HSCT, the highest risk is in patients with severe GVHD (grade III-IV). In a study by Marr et al., the probability of IPA following allogeneic HSCT reached approximately 5% at 2  months, 9% at 6 months and 10% at 1 year following allogeneic HSCT. By the third year after transplantation, the probability of IPA increased minimally to 11.1% [50]. In these patients, the timeline for IPA infection follows a bimodal distribution, with a peak in the first month following HSCT, which is associated with neutropenia. The second peak is during the treatment for GVHD (median 78–112  days post transplantation) [49, 51, 53]. The first peak is currently less significant due to the routine use of stem cell instead of bone marrow for transplantation, non-myeloablative regimens, the use of colony-stimulating factors during neutropenia and the widespread use of antifungal agents have significantly decreased the incidence of IPA during this period [49, 54]. On the other hand, the incidence of IPA during the treatment of GVHD has become more significant, especially with higher incidence of GVHD associated with unrelated allogeneic transplantation and nonmyeloablative HSCT. Cord blood HSCT is also associated with increased risk of IPA. In one study of patients who received low intensity cord blood transplantation, the 3-year accumulative incidence of IPA

A.O. Soubani

was 10% with mortality of 86%. All of these patients developed IPA in the first 100 days post transplantation (median 20 days) [55]. Also the risk of IPA increases with the use of Alemtuzumab, which is an anti-DC52 monoclonal antibody used to deplete peripheral B and T lymphocytes [49, 50, 52]. Treatment of GVHD with intensive immunosuppressive therapy, including corticosteroids, cyclosporine A and anti-TNF- a agents, further increases the risk of IPA [49, 50, 56–58]. There is also evidence that CMV infection in these patients increases the risk of IPA [50, 59]. The hazards ratio for IPA in the setting of CMV disease increases by 13.3 folds (95% CI 4.7–37.7) [51]. A recent retrospective review of 385 cases of suspected or documented IPA in patients with hematological malignancies over a 9-year period revealed that the overall and disease-specific survival rates were 52% and 60%, respectively. Factors that predicted mortality were allogeneic HSCT, neutropenia, progression of the underlying malignancy, prior respiratory disease, corticosteroids therapy, renal impairment, low monocyte counts, disseminated aspergillosis and pleural effusion [60]. Aspergillus is most often introduced to the lower respiratory tract by inhalation of the infectious spores. Less commonly, IPA may start in locations other than the lungs, like sinuses, the gastrointestinal tract, or the skin (intravenous catheters or prolonged skin contact with adhesive tapes) [61–64]. Patients present with symptoms that are usually non-specific and consistent with bronchopneumonia, with fever unresponsive to antibiotics, cough, sputum production and dyspnea. Patients may also present with pleuritic chest pain (due to vascular invasion leading to small pulmonary infarcts) and hemoptysis, which is usually mild, but could be massive. IPA is one of the most common causes of hemoptysis in neutropenic patients and has been reported to be associated with cavitation that occurs with neutrophil recovery [65]. Aspergillus infection may also disseminate hematogenously to other organs, most commonly the brain (leading to seizures, ringenhancing lesions, cerebral infarctions, intracranial hemorrhage, meningitis and epidural abscess), and less frequently other organs such as skin, kidneys, pleura, heart, esophagus and liver may be involved [66]. The diagnosis of IPA is challenging. Early diagnosis of IPA in patients with hematological malignancies remains difficult, and a high index of suspicion is necessary in patients with risk factors for invasive disease. Histopathological diagnosis by examining lung tissue

3  Respiratory Infections in Patients with Hematological Malignancies

19

obtained by surgical lung biopsy remains the “gold standard” for the diagnosis of IPA [67]. The presence of septate, acute, branching hyphae invading the lung tissue samples along with a culture that is positive for Aspergillus species from the same site is diagnostic of IPA. Histopathological examination also allows for the exclusion of other diagnoses, such as malignancy or nonfungal infectious diseases. The histopathological findings associated with IPA have been recently shown to differ according to the underlying host. In patients with allogeneic HSCT and GVHD, there is intense inflammation with neutrophilic infiltration, minimal coagulation necrosis and low fungal burden. On the other hand, IPA in neutropenic patients is characterized by scant inflammation, extensive coagulation necrosis associated with hyphal angioinvasion and high fungal burden. Dissemination to other organs is equally high in both groups [68]. The chest radiograph has a small role in early stages of the disease because the incidence of non-specific changes is high. Usual findings include rounded densities, pleural-based infiltrates that are suggestive of pulmonary infarctions and cavitations. Pleural effusions are uncommon [69, 70]. Chest CT scan, especially when combined with high-resolution images, is a much more helpful tool in the diagnosis of IPA. The routine use of high-resolution CT of the chest early in the course of IPA has been shown to lead to earlier diagnosis and improved outcome of these patients [71, 72]. It also aids further diagnostic studies such as bronchoscopy and surgical lung biopsy [73]. The typical chest CT scan

findings in patients suspected to have IPA include: multiple nodules and the halo sign, which is mainly seen in neutropenic patients early in the course of infection (usually in the first week), and appears as a zone of low attenuation due to hemorrhage surrounding the pulmonary nodule (Fig. 3.4). Another late radiological sign is the air crescent sign, which represents crescent-shaped lucency in the region of the original nodule secondary to necrosis [70, 74]. Neither the halo nor the air crescent signs are sensitive to or pathognomic of IPA. The halo sign may be found as a result of metastasis, organizing pneumonia or other fungal infection [75]. Greene et al. found that 94% of 235 patients with a confirmed diagnosis of IPA had at least one nodular region [76]. In another recent report of 27 patients with IPA following allogeneic HSCT, the most common radiological findings were ill-defined consolidation (48%), nodules with halo sign (44%), centrilobular nodules (44%), groundglass-attenuation (22%) and pleural effusion (26%) [77]. In a large study of 236 patients with IPA, 86% of whom had hematological malignancies, the halo sign was detected in 61% of the cases. In the study population as a whole, and specifically in patients with hematological malignancies, the presence of the halo sign predicted better response to antifungal therapy [78]. On the other hand, in a retrospective study done on 45 patients, Horger et al. found that none of the early highresolution CT scan signs (nodule, consolidation, peribronchial infiltrates) seems to predict patient outcome or the development of pulmonary hemorrhage [79]. However, pulmonary hemorrhage is expected to occur

Fig. 3.4  (a) High resolution CT scan of the chest showing right upper lobe nodule with the Halo sign in a patient with nonHodgkin’s lymphoma and neutropenia who developed IPA.

(b) Shows residual cavity formation after 2 months of treatment with antifungal agent

20

in the presence of large cavitating nodules or consolidations located close to larger pulmonary vessels. The significance of isolating Aspergillus species in sputum samples depends on the immune status of the host. In patients with hematological malignancies, isolation of Aspergillus species from sputum is highly predictive of invasive disease. Studies have shown that sputum samples that are positive for Aspergillus in these patients have a positive predictive value of 80–90% [80–82]. However, sputum samples that are negative could not rule out IPA, since negative sputum studies have been noted in 70% of patients with confirmed IPA [82, 83]. Blood cultures are rarely positive in patients with confirmed IPA [84]. Bronchoscopy with BAL is generally helpful in the diagnosis of IPA, especially in patients with diffuse lung involvement. Visualization of the bronchial tree may also provide arguments for IPA in patients with airway-invasive IPA. The sensitivity and specificity of a positive result of BAL fluid are around 50% and 97%, respectively. The yield of BAL in the diagnosis of IPA is not consistent, and there are reports of much lower diagnostic yield [80, 81, 85–89]. BAL is generally a safe and useful tool in non-hypoxemic patients with hematological malignancies suspected to have IPA. In addition to obtaining samples for fungal stain and culture, it may be useful in detecting Aspergillus antigens in the BAL fluid and excluding other infections. Transbronchial biopsies usually do not add much to the diagnosis of IPA and are associated with increased risk of bleeding, so they are usually not performed [80]. In the setting of diagnostic workup for IPA, it is important to send samples such as sputum, BAL fluid or lung tissue for culture as well as for histological examination. This is because other fungal species, such as scedosporium, pseudallescheria and fusarium, may have a similar histological appearance as Aspergillus [90]. Furthermore, there are different species of Aspergillus that may lead to IPA. While Aspergillus fumigatus is the most common cause of IPA, there are increasing reports of IPA in patients with hematological malignancies due to other species such as A. niger, A. terreus and A. flavus [91–95]. Some of these species (such as A. terreus and A. nidulans) are resistant to amphotericin B [92, 95]. In a review of 300 patients with hematological malignancies (40% were HSCT recipients) with proven IPA, A. terreus was the second most common species isolated with a frequency of 23%. The risk factors and outcome for A. terreus infection were similar to those for A. fumigatus infection;

A.O. Soubani

however the former was significantly more likely to be nosocomial in origin and more likely to be resistant to amphotericin B [94]. The new triazole antifungal agents such as voriconazole and posaconazole have significantly better efficacy against A. terreus [92, 93, 96]. The most recent advances in the diagnosis of IPA are related to detecting Aspergillus antigens in body fluids. Galactomannan (GM) is a polysaccharide cellwall component that is released by Aspergillus during growth. A double-sandwich ELISA for the detection of GM in serum was approved by the Food and Drug Administration for the diagnosis of IPA, with a threshold of 0.5 ng/mL. It is reported that serum GM can be detected several days before the presence of clinical signs, an abnormal chest radiograph or positive culture. Thus, GM detection may allow earlier confirmation of the diagnosis, and serial determination of serum GM values may be useful in assessing the evolution of infection during treatment [97, 98]. A meta-analysis study was undertaken by Pfeiffer et al. to assess the accuracy of a GM assay in diagnosing IPA. Twenty-seven studies from 1996 to 2005 were included, and cases were diagnosed to have IPA according to the European Organization for Research on Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria. Overall, the GM assay had a sensitivity of 71% and specificity of 89% for proven cases of invasive aspergillosis. The negative predictive value was 92–98%, and the positive predictive value was between 25% and 62% [99]. Pfeiffer and colleagues concluded that GM assay is more useful in patients who have hematological malignancies or who have undergone allogeneic HSCT than in solid-organ transplant recipients or nonneutropenic patients. GM is found in food and may be absorbed by the digestive tract, especially in patients with postchemotherapy mucositis, resulting in a false-positive reaction. Also medications such as b-lactam antibiotics (e.g., piperacillin/tazobactam) may be associated with false-positive GM assay, while antifungal agents with activity against Aspergillus may lead to a false-negative test [100–103]. It is noteworthy that GM assay is species specific, and it is not possible to exclude the involvement of other molds such as Fusarium, Zygomycetes and dematiaceous fungi by measuring serum GM [104]. There is evidence that GM is detected in other body fluids such as BAL, urine and cerebrospinal fluid, and that these tests may become positive prior to clinical and radiological findings suggestive of IPA [104–107].

3  Respiratory Infections in Patients with Hematological Malignancies

A recent prospective study of 200 patients with hematological malignancies and profound neutropenia found that GM assay from BAL had a sensitivity of 100% for IPA compared to 71% by serum GM assay [108]. Another study done by Musher et  al. showed that incorporating GM assay and quantitative PCR assay into standard BAL fluid analysis may enhance bronchoscopic identification of Aspergillus species as the cause pulmonary disease in patients with hematological malignancies [105]. Serial serum GM assay has also been shown to help in the early detection of IPA and as a surrogate to response to therapy. In a study of 70 neutropenic patients with IPA, serum GM assay was performed three times weekly after the start of antifungal therapy until GM index negativity or death. The patients who had normalization of the serum GM index did significantly better than those who continued to have positive serum GM [109]. Polymerase chain reaction (PCR) is another way to diagnose IPA by the detection of Aspergillus DNA in BAL fluid and serum. A positive Aspergillus PCR in BAL fluid has an estimated sensitivity of 67–100% and specificity between 55% and 95% [110]. PCR sensitivity and specificity have also been reported as 100% and 65–92%, respectively, in serum samples [110–113]. However, this test is often associated with false-positive results because it doesn’t discriminate between colonization and infection. PCR for Aspergillus nucleic acid detection remains restricted to highly specialized laboratories and cannot be considered as a routine exam. Detection of serum (1 → 3)-b-d-glucan, a fungal cell wall constituent, has recently received Food and Drug Administration approval. Determination of plasma (1 → 3)-b-d-glucan has been reported to be a highly sensitive and specific test for invasive deep mycosis, including candidiasis, fusariosis, Pneumo­cystosis and aspergillosis, and could be useful in the immunocompromised patients [114]. A prospective study of 95 patients with hematological malignancies and neutropenia evaluated the value of monitoring the serum level of (1 → 3)-b-d-glucan twice weekly in the absence of fever and daily in the presence of fever in the early diagnosis of IPA. Thirteen patients developed IPA, 15 patients had candidiasis, and 2 patients had mixed invasive fungal infections. The sensitivity, specificity, positive predictive value and negative predictive value of two consecutive positive (1 → 3)-b-d-glucan values were 0.63, 0.96, 0.79 and 0.91, respectively [115]. The utility of routine monitoring of this assay in patients with hematological malignancies at high risk for IPA is not yet defined.

21

The role of GM and other serological studies in the diagnosis of IPA is evolving. Furthermore, their role in different hosts, as surveillance tools, and their impact on the outcome of patients are not clear. There are ongoing prospective studies to address these issues. Until solid data are available, these tests should be considered as adjunct diagnostic studies, and should not replace appropriate clinical and radiological evaluation, and in selected cases, invasive procedures to confirm the diagnosis of IPA. The EORTC/MSG has revised its criteria for the diagnosis of invasive fungal infections [116, 117]. These criteria consist of host factors, microbiologic, minor and major clinical criteria (Table 3.5). Positive serum GM, with the appropriate host and clinical Table 3.5  The diagnostic criteria for IPA Diagnosis Criteria Proven IPA

Histopathologic or cytopathologic examination of lung tissue showing hyphae from needle aspiration or biopsy specimen with evidence of associated tissue damage; OR Positive culture result for Aspergillus from a sample obtained by sterile procedure from the lung and clinically or radiologically abnormal site consistent with infection

Probable IPA

Host risk factora; AND Microbiological criteria (positive Aspergillus microscopy or culture from the sputum or BAL, or positive GM assay); AND Clinical criteria consistent with the infection (1 major or 2 minor)b

Possible IPA

Host risk factor; AND Microbiological criteria (positive Aspergillus microscopy or culture from the sputum or BAL, or positive GM assay from one BAL or at least two serum samples); OR Clinical criteria consistent with the infection (1 major or 2 minor)a

At least one of the following host factors include neutropenia (<500 cells/mm3 for >10  days), allogeneic HSCT, prolonged corticosteroid therapy (>0.3 mg/kg/day of prednisone or equivalent for >3 weeks); T cell suppressant therapy b Major clinical criteria are: new characteristic infiltrates on CT imaging (halo sign, air-crescent sign, or cavity within area of consolidation). Minor clinical criteria are: Symptoms of LRTI (cough, chest pain, hemoptysis, or dyspnea); physical finding of pleural rub; any new infiltrate not fulfilling major criterion; pleural effusion a

22

factors, can be considered as “probable” IPA. The EORTC/MSG criteria are not evidence-based and are not prospectively validated. Instead, they are meant to serve as a guide for clinical and epidemiological research and need not be present in every patient to treat for IPA. The treatment of IPA is difficult, and the mortality rate is still high despite the introduction of several new antifungal agents. Herbrecht and colleagues report in this book a very comprehensive and up-to-date contribution on antifungal agents. Therapy should be considered as soon as there is a clinical suspicion of IPA and while a workup is underway. For many years, amphotericin B has been the first line of therapy for IPA. The recommended dose is 1–1.5 mg/kg/day. Amphotericin B is known, however, to cause serious side effects, including nephrotoxicity, electrolyte disturbances and hypersensitivity. For these reasons, this agent nowadays has little role to play in the treatment of IPA, and newer lipid-based preparations of amphotericin B (e.g., liposomal amphotericin B and lipid complex amphotericin B) have been introduced to minimize these side effects. Higher doses of the lipid formulations are needed for equivalent antifungal efficacy to amphotericin B. Voriconazole is a new broad-spectrum triazole that is approved as the initial treatment of invasive aspergillosis and is currently considered the treatment of choice in many patients with IPA [118–120]. In a large prospective, randomized, multicenter trial, voriconazole was compared to amphotericin B as the primary therapy for IPA [121]. Patients receiving voriconazole had a higher favorable response rate at week 12 (53% compared with 32% in patients receiving amphotericin B) and a higher 12-week survival (71% compared with 58%). Voriconazole is available in both intravenous and oral formulations. The recommended dose is 6 mg/kg twice daily intravenously on day 1 followed by 4  mg/kg/day. After 7  days, switching to 200  mg orally twice daily may be considered. Voriconazole has a milder side effect profile and is much better tolerated than amphotericin B. The most frequent adverse effect is visual disturbances described as blurred vision, photophobia and altered color perception. Liver function test abnormalities and skin reactions are less common side effects associated with voriconazole treatment. It is important to note that voriconazole is associated with a significant number of drug-drug interactions such as cyclosporine, warfarin, terfenadine, carbamazepine, quinidine, rifampin, statins and sulfonylureas [118].

A.O. Soubani

Posaconazole is another broad-spectrum triazole that has been shown to be effective and safe as salvage therapy in patients with invasive aspergillosis refractory to standard antifungal therapy [96, 122, 123]. Echinocandin derivatives such as caspofungin, micafungin and anidulafungin are effective agents in the treatment of IPA refractory to standard treatment or if the patient could not tolerate first line agents [124, 125]. In its recent guidelines, The Infectious Disease Society of America recommends voriconazole as the primary treatment for IPA in most patients and liposomal amphotericin B as an alternative treatment for some patients. For salvage therapy, agents include lipid-based preparations of amphotericin A, posaconazole, itraconazole, caspofungin or micafungin [126]. Some studies have suggested that combination antifungal therapy could be a strategy to treat refractory IPA [127, 128]. There are no prospective randomized studies that show superior efficacy of combination therapy over a single agent in the primary management of IPA. There are in  vitro and limited clinical studies in the form of case reports and retrospective case series that show a benefit from combining antifungal agents as salvage therapy in refractory IPA [128–131]. The combination of caspofungin and liposomal amphotericin B as a salvage therapy showed an overall response rate of 42%; however, in patients with progressive documented IPA, the response rate was only 18% [128]. A survival advantage of voriconazole plus caspofungin compared with voriconazole alone was reported by Marr et al. in a retrospective analysis of salvage therapy for IPA [130]. On the other hand, the report by Denning et al. showed no difference in the response rate between patients who received micafungin alone or in combination with other antifungal agents as primary or salvage therapy for IPA [132]. Combination therapy of an echinocandin with either a lipid formulation of amphotericin B or triazole agent appears to be promising, however cannot be recommended for the routine treatment of primary IPA. Controlled randomized prospective studies are needed to document the value of this approach. Surgical resection has a limited role in the management of patients with IPA; however, it should be considered in cases of massive hemoptysis or pulmonary lesions close to the great blood vessels or pericardium, or the resection of residual localized pulmonary lesions in patients with continuing immunosuppression. Several reports have shown the relative efficacy and safety of surgical intervention – in

3  Respiratory Infections in Patients with Hematological Malignancies

addition to antifungal therapy – in these situations [72, 133–138]. Immunomodulatory therapy, such as using colonystimulating factors (i.e., granulocyte-colony stimulating factors, granulocyte macrophage-colony stimulating therapy) or interferon-g, could be used to decrease the degree of immunosuppression and as an adjunct to antifungal therapy for the treatment of IPA. Colonystimulating factors stimulate the bone marrow to produce more neutrophils and have been shown to augment the phagocytic activity of neutrophils against fungi, including Aspergillus species [139–141]. There is a theoretical advantage to adding these agents to the treatment of neutropenic patients suspected to have IPA. In one randomized study in patients receiving chemotherapy for acute myelogenous leukemia, prophylaxis with GM-CSF led to a lower frequency of fatal fungal infections compared with placebo (1.9% vs. 19%, respectively) and reduced overall mortality [142]. It is recommended to consider colony-stimulating factors in neutropenic patients with serious infections; however, there are no definitive studies that show benefit in patients with IPA [143]. Interferon-g is another cytokine that has been shown in vitro and in animal models to augment immunity by increasing neutrophil and monocyte activity against Aspergillus [140, 144, 145]. The value of adding interferon-g as an adjunct treatment of IPA is limited to case reports and small reports, and there are no guidelines on its role in the treatment of IPA [146]. There was a concern about the use of interferon-g in allogeneic HSCT recipients, since it may worsen GVHD; however, a recent trial showed that GVHD may actually improve during this therapy [147]. Granulocyte transfusion is another potential supportive therapy for patients with prolonged neutropenia and life-threatening infections refractory to conventional therapy. It has been shown that it is safe for potential donors to donate neutrophils by granulocytophoresis; however, there are no randomized studies that prove the benefit of adjuvant granulocyte transfusion in the treatment of IPA [148]. A review of 66 observational studies of patients who received ganulocyte transfusions, either prophylactic or therapeutic, in the management of gram-negative bacterial or fungal infections suggested survival in 70% [149]. It is also important in patients with IPA, whenever possible, to decrease the dose of systemic corticosteroids and immunosuppressive agents. The management of IPA is difficult and an important approach to this problem is prophylaxis for those patients

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who are at increased risk for this infection. Avoiding the hospitalization of patients in areas where there are construction and the use of high-efficiency particulate air (HEPA) filtration with or without laminar air flow ventilation have proven to be efficient [150]. A meta-analysis suggested that itraconazole was effective in preventing fungal infections in neutropenic patients [151]. Recent data also suggest the efficacy of posaconazole in the prophylaxis against IPA in patients with severe GVHD and other hematological malignancies [152, 153]. There are also preliminary data that suggest aerosolized treatment with antifungal agents such as liposomal amphotericin B and voriconzaole may be effective in the prevention of IPA in high risk population [154, 155].

3.4.2 Other Fungi Other fungal infections may invade the lungs in hematological patients. An entire chapter on emerging fungal infections from Drs. Garnica and Nucci is provided in this book. These invasive fungal infections primarily involve the lungs, but may disseminate to other organs. They are mainly seen in patients with neutropenia, allogeneic HSCT, and GVHD [52, 156–159]. The main invasive fungal infections that are reported in these patients include hyaline hyphomycetes (such as fusarium and Scedosporium), zygomycetes and endemic fungi. In a Centers for Disease Controlsponsored surveillance program for invasive fungal infections, there were 886 patients with invasive fungal infections out of 20,000 HSCT and solid organ transplant recipients [160]. Non-apsergillus molds were responsible for 14% of infections, cryptococcus in 4%, endemic fungi in 3% and pneumoystis in 2%. Hyaline hyphomycetes, such as fusarium and scedosporium, are the main non-aspergillus molds that are reported in patients with hematological malignancies. These organisms resemble Aspergillus histolo­gically with septate hyphae that invade blood vessels [52, 161, 162]. Culture is the only means to distinguish these organisms from Aspergillus. The lungs are the primary site of infection; however, these organisms have the tendency to disseminate. In one study, fusarium infection involved the lungs in 81% of the cases, and was disseminated in 74% of the patients [52]. Fungemia due to fusarium is reported in 20–70% of patients [163]. These infections usually occur early (in the first 2 months) following allogeneic HSCT. The mortality

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in patients with pulmonary fusariosis is 65% within 1 month of diagnosis [164]. Factors that decrease survival are persistent neutropenia and corticosteroid therapy. Scedosporium has been isolated from the air in hospitals [162]. In the lungs, these organisms usually present with thin wall cavities or nodules with or without air-crescent sign that are refractory to antibiotics and antifungal therapy [165]. The diagnosis is usually confirmed by isolating the organisms by culture of BAL fluid or lung tissue obtained by surgical lung biopsy. Occasionally the diagnosis is obtained by fungal blood cultures. Mortality associated with these fungal infections remains very high, in the range of 70–100% [163, 166–168]. Zygomycetes such as Rhizopus and mucor are characterized by sparsely septate, broad hyphae with irregular branching. They have the tendency to invade blood vessels with thrombosis and tissue necrosis. They usually involve the sinopulmonary tree; however dissemination to other organs is rare. The incidence of zygomycetes infections in patients with hematological malignancies is rare (0.5–1.9%) [52, 158, 159]. It is important to note that these organisms may be resistant to voriconazole [169]. Recent reports suggest good response to posaconazole [170]. Mortality associated with zygomycetes infection in patients with hematological malignancies reaches 80% [52, 158, 159]. Cryptococcus infection in patients with hematological malignancies has been rarely reported. The widespread prophylaxis with fluconazole may account for the relatively low incidence in these patients. Patients with profound T cell depression (such as Hodgkin’s disease, chronic leukemia and treatment with purine analogues) are at highest risk [171]. The diagnosis of pulmonary cryptococcal infection is usually made by detection of the fungus in BAL or lung tissue samples. Serum cryptococcal antigen has more than 95% sensitivity and specificity in the diagnosis of invasive cryptococcosis, however could be negative in patients with localized pulmonary infection [172]. The treatment of pulmonary cryptococcosis in hematological malignancies includes Amphotericin B for severe cases, and fluconazole or itraconazole for milder cases and for maintenance therapy [173]. As reported in the chapter from Carvajal et al., invasive Candida infection develops in 11–16% of patients with hematological malignancies, and pulmonary involvement is usually secondary to disseminated

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candidiasis or candidemia. Autopsy studies suggest that 50% of infected patients have pulmonary involvement [174]. In a study of 529 patients who died from leukemia or myelodysplastic syndrome and were affected by candidiasis, 45% had lung involvement. It is believed that Candida may have disseminated to all organs, including the lungs, prior to their death [175]. Primary Candida pneumonia is extremely rare. Histopathological confirmation is necessary in most of the cases. The universal prophylaxis with fluconazole has significantly decreased the incidence of Candida infections. However, there is a shift in the Candida species from Candida albicans to more resistant species such as C. glabrata or C. krusei. As reported in the dedicated chapter, Pneumocystis pneumonia is caused by P. jiroveci, which is a fungal agent [176]. Infection is caused by inhalation of aerosolized organisms. The incidence of P. pneumonia was historically up to 20% of patients with hematological malignancies and 5–15% of HSCT recipients [4, 177]. However, the routine prophylaxis with TMX/ SMZ during high-risk periods has significantly decreased the incidence of this infection to negligible values. Breakthrough infection in patients on TMP/ SMZ prophylaxis is extremely rare, however is possible in patients on other prophylactic agents such as low-dose atovaquone or aerosolized pentamidine [178–180]. Patients with lymphoproliferative disorders appear to be at the highest risk for P. jiroveci infection. Also the prolonged administration of high-

Fig. 3.5  High resolution CT scan of the chest showing diffuse ground glass infiltrates in a patient with non-Hodgkin’s lymphoma on chemotherapy who developed P jiroveci pneumonia

3  Respiratory Infections in Patients with Hematological Malignancies

dose corticosteroid therapy and purine analogues such as fludarabine–especially when combined with corticosteroids–significantly increase the risk of this infection [181–184]. In a recent report of 519 allogeneic HSCT recipients, P. jiroveci pneumonia was documented in 13 patients (2.5%). The majority of cases occurred late in the course following HSCT (median 14.5  months) after discontinuation of prophylactic agents [185]. The CD4+ T cell count was low, and 70% of patients were on immunosuppressive therapy for chronic GVHD. The onset of P. jiroveci pneumonia is acute and rapidly progressive in the majority of cases, with dyspnea, nonproductive cough and fever. Hypoxemia is usually dramatic in these patients [183]. Radiologically, there are perihilar interstitial or alveolar infiltrates. Groundglass opacities may be the prominent finding on highresolution CT scan of the chest (Fig. 3.5). LDH may be elevated. The diagnosis is usually made by bronchoscopy with BAL; however, the sensitivity of this procedure is lower than that reported in patients with AIDS due to the lower burden of the organism [4]. Monoclonal antibodies for detecting P. jiroveci have higher sensitivity and specificity in induced sputum samples than conventional staining, but the difference between the two methods is insignificant in BAL fluid [186, 187]. Mortality has been recently reported to be 20% of patients with cancer, and the only predictor of poor outcome based on multivariate analysis was the need for mechanical ventilation [188, 189]. Prophylaxis against P. jiroveci pneumonia using TMP/SMZ is recommended for patients who are on chronic corticosteroid therapy and following engraftment in allogeneic HSCT recipients for 120 days. However, if the patient has chronic GVHD, prophylactic treatment is recommended as long as they are on immunosuppressive therapy for this condition. Endemic mycoses, such as histoplasmosis, blastomycosis and coccidiomycosis, are rare in patients with hematological malignancies [190]. These infections tend to have geographical distribution and are usually caused by endogenous reactivation of a latent infection. The infection usually presents with progressive pulmonary disease that disseminates to other organs. Treatment is with a high-dose amphotericin B preparation [161]. After controlling the infection, an azole such as itraconazole (or fluconazole in the case of coccidiomycosis) can be used as a maintenance treatment [160].

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3.5 Cytomegalovirus It is important at the outset to define the different manifestations of CMV infection. CMV infection is defined as isolation of the CMV virus or its proteins or nucleic acid from body fluids or tissue specimens. CMV viremia is isolation of CMV from blood by culture. CMV antigenemia is detection of CMV pp65 in circulating leukocytes or CMV DNA by PCR techniques. CMV disease is the presence of signs and symptoms related to CMV infection, and may manifest as hepatitis, ­gastroenteritis, encephalitis or a systemic syndrome. CMV pneumonia is one of the most frequent and severe manifestations of CMV disease in patients with hematological malignancies, especially HSCT recipients. It is defined as pulmonary signs and symptoms combined with detection of CMV in pulmonary samples (BAL or lung tissue). It is important to note that some patients may shed CMV in BAL fluid in the absence of invasive disease. It is also significant to note that CMV affects the immune system and promotes other infections. Co-infection with other organisms, such as bacteria, P. jiroveci, Aspergillus or other viruses, is reported in up to one third of cases [191]. An entire very nice contribution from Dr. Vigil and Chemaly in this book provides a comprehensive ­overview on CMV pneumonia. Traditionally, CMV pneumonia was a relatively frequent infection in patients with hematological malignancies. It was diagnosed in 20–35% of allogeneic HSCT recipients and 60–80% of patients with diffuse pneumonitis following HSCT [29, 192, 193]. CMV pneumonia usually presented in the first 2  months post-transplantation (median 44 days), and was associated with high mortality ranging between 80% and 100% [192]. However, antiviral prophylaxis for high-risk patients and preemptive therapy has changed the epidemiology of CMV pneumonia in HSCT recipients. Currently in allogeneic HSCT recipients, the incidence of CMV pneumonia is about 10%, while in autologous recipients, CMV pneumonia is extremely rare (1–9%) [194– 197]. An autopsy-based case control study evaluated the incidence and risk factors of fatal CMV pneumonia in patients with hematological malignancies. The incidence of fatal CMV pneumonia was 3.5% before 1997 compared to 0.8% after that date. Complete remission of the underlying malignancy and sustained lymphopenia were independent predictors of CMV pneumonia [198]. Prophylactic and preemptive antiviral therapy

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has also shifted the onset of CMV pneumonia in allogeneic HSCT to after the first 100  days (median 169 days), especially in patients with non-myeloablative HSCT and during the treatment of chronic GVHD [199, 200]. The risk of CMV pneumonia in patients with hematological malignancies is mainly seen in patients with leukemia or lymphoma who are on T-cell-depleting chemotherapeutic regimen (such as ­cytarabine, fludarabine, high-dose cyclophosphamide, corticosteroids or alemtuzumab). In HSCT recipients, CMV pneumonia is mainly seen after allogeneic transplantation and the highest risk is in seropositive recipients. CMV disease is reported in 14% of seropostive recipients who received a seropositive graft and in 12% of seropositive recipients and seronegative grafts. On the other hand, the risk of CMV disease is lower in seronegative recipients who had HSCT from seropositive donors (incidence is less than 5%) [201]. Additional risk factors for CMV pneumonia include older age, total body irradiation, myeloablative chemotherapy, the presence and acuity of acute GVHD, and the use of T-cell depletion strategies [192, 202, 203]. In autologous HSCT, the main risk factors for CMV pneumonia are the presence of CMV infection prior to transplantation, CD-34-enriched stem cells, probably due to lower number of T cells and delayed immunologic reconstitution [204]. CMV pneumonia presents clinically with rapid onset of fever, nonproductive cough, dyspnea and hypoxemia. Pleurisy may be present. The respiratory symptoms usually progress to acute respiratory failure within 2 weeks. Radiologically, the most common findings are an interstitial pattern with tiny pulmonary nodules and patchy areas of consolidation. Rarely CMV pneumonia may present with focal diseases [205, 206]. High-resolution CT scan of the chest is more sensitive in detecting the findings related to CMV pneumonia including diffuse or patchy groundglass opacification, thickened interlobular septa and tree in bud nodular changes. Pleural effusion may be present in around quarter of patients [206]. The differential diagnosis of these clinical and radiological findings includes P. jiroveci, other viral infections, pulmonary hemorrhage, drug-induced lung injury, pulmonary edema or tumor recurrence. Some of these conditions may co-exist with CMV pneumonia. The hallmark of the histopathological findings of CMV pneumonia is demonstrating the intracytoplasmic inclusion bodies within areas of inflammation on lung

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biopsy. These eosinophilic bodies may be absent early in the process. There are also areas of mononuclear interstitial pneumonitis with or without alveolar epithelial desquamation and hyaline membrane formation. These findings can be rarely demonstrated by bronchoscopic biopsy; however, usually surgical lung biopsy by video-assisted thoracoscopy is necessary. Cytological examination of the BAL fluid to detect the inclusion bodies within the lower respiratory tract epithelial cells is highly specific (98%) for CMV pneumonia, but has low sensitivity, with a positivepredicted value of 73% and a negative predictive value of 99.5% [207]. On the other hand, rapid culture of the BAL fluid using the shell viral technique is highly sensitive (99%) in detecting the virus, but lacks the specificity (67–83%), since it cannot differentiate between viral shedding and invasive disease [207, 208]. The value of detecting CMV antigens in the diagnosis of CMV pneumonia is controversial. CMV pp65 antigen assay is based on staining blood neutrophils for the pp65 antigen. The test requires an adequate number of neutrophils (>1,000 cells mm3), so it is not useful in the presence of neutropenia [209]. Another way to quantitatively measure CMV viral load is by detecting the viral DNA by PCR, which could be done on whole blood, plasma, leukocytes, BAL, urine and CSF. Detection of CMV viral DNA in the BAL fluid is suggestive of CMV pneumonia; however, false-positive results are frequent [210]. Detecting blood CMV antigens–by either method– correlates well with CMV pneumonia [211, 212]. However, it is possible for CMV pneumonia to develop without antigenemia [213]. CMV antigens in blood samples may precede clinical features of CMV pneumonia by up to 3  weeks [214]. These tests are also useful in monitoring the response to antiviral therapy. Persistence of CMV antigenemia after 2  weeks of therapy should raise suspicion of antiviral resistance. Gancyclovir as a single agent or in combination with CMV immunoglobulins has been shown to be effective in uncontrolled trials in the treatment of CMV pneumonia and is currently the standard of care in the management of this condition [194, 197]. This is reported in the reviews from Dr. Vigil and from Dr. Sandherr. With this approach, mortality has decreased to 0–47% provided treatment is started prior to the onset of acute respiratory failure. Survival of patients with respiratory failure at the time of initiation of therapy remains infrequent. Prevention of CMV

3  Respiratory Infections in Patients with Hematological Malignancies

infection is the best approach to avoid disease. Use of CMV negative stem cells for HSCT and seronegative or leukocyte-filtered blood products for CMV seronegative recipients decreases the risk of infection to 2–4% [215–217]. Antiviral prophylaxis and viral monitoring with pre-emptive therapy are at present the two main antiviral strategies used in the prevention of CMV infection and disease. Gancyclovir prophylaxis administered in seropositive patients or in seronegative subjects receiving graft from a seropositive donor from 5 days before engraftment to 100 days after HSCT reduces the risk of CMV infection and invasive disease, as well as mortality [218]. However, this approach did not change the overall survival owing to increased sepsis associated with gancyclovir-induced neutropenia and shift in the onset of the CMV disease later in the course following HSCT when the prophylactic treatment is discontinued [219]. Valgancyclovir showed promise as an alternative antiviral agent for preemptive treatment of CMV reactivation following allogeneic HSCT [220]. The use of a cutoff of the number of CMV DNA copies in whole blood samples (10,000 DNA copies/ml) may be useful in avoiding unnecessary antiviral treatment [221]. Other interventions that are under evaluation include infusion of donor-derived CMV-specific cytotoxic T lymphocyte infusion and CMV vaccine [222].

3.6 Community Respiratory Viruses There are four community respiratory viral agents that commonly lead to serious infection in patients with hematological malignancies. These are respiratory syncytial virus (RSV), parainfluenza, influenza and adenovirus. In this book, Schnell and coworkers provide a comprehensive overview on pneumonia related to common viruses in hematological patients. The data on the significance of community respiratory viral infections in this patient population are limited for several reasons, including reports based on small case series, the seasonal nature of the infection that may change the frequency of these infections depending on the time and location of the study, and the fact that many of the patients with community respiratory viral infections are asymptomatic. Nevertheless, there have been recent large studies that improved our understanding of the role of community respiratory viral infections in

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patients with hematological malignancies, especially those who underwent HSCT. Overall, it appears that the incidence of these viral infections in patients with hematological malignancies ranges between 11 and 65% [223–226]. In one study of community respiratory viral infections following HSCT, the main viruses were RSV (35%), parainfluenza (30%), rhinovirus (25%) and influenza virus (11%). Of these, pneumonia occurred in 49% of patients with RSV infection, 22% of those with parainfluenza virus and 3% of rhinovirus infection [227]. In another recent review of 343 cases of community respiratory viral infections in 306 adult patients with hematological malignancies, parainfluenza (mainly type 3) accounted for 27% of infections, influenza (mainly type A) in 33% of infections and RSV in 31% of infections. Community respiratory viral infections progressed to pneumonia in 35% of patients with equal frequency among the three viruses. The patients at high risk for community respiratory viral infections included allogeneic HSCT, leukemia, age older than 65 years, and presence of severe neutropenia or lymphopenia. The overall mortality for community respiratory viral pneumonia was 15%. The only independent predictor of fatal outcome was absolute lymphopenia in patients with influenza pneumonia [226]. The diagnosis of lower respiratory tract community respiratory viral infection is usually suspected in patients with preceding upper respiratory tract infection. The high-resolution CT scan of the chest usually shows patchy or extensive ground-glass opacities, or a mixture of patterns including ground-glass attenuation, thickening of the bronchial walls, and multiple small nodules that may have centrilobular or random distribution. Consolidation and pleural effusions are less common [228]. The diagnosis is usually made using the combination of direct fluorescent antibody (DFA) and indirect fluorescent antibody (IFA) testing, and viral cultures of clinical specimens. The results of the former tests are usually available within 24 h, whereas cultures usually take 7–14 days. The clinical specimens are best obtained by nasopharyngeal wash or swabs. The sensitivity of direct DFA and IFA in detecting infection in patients with hematological malignancies ranges between 20% and 52% [229–231]. BAL fluid may also be helpful when lower respiratory tract infection is suspected with a sensitivity of around 70% [225]. It is important to note in this context that community respiratory viruses are often co-pathogens with other organisms, including bacteria, fungi (such as

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Aspergillus and P. jiroveci) or other viruses (such as CMV) [232]. In one study of community respiratory viral pneumonia, 119 patients had BAL specimens, and 14% had other pathogens cultured [226]. This may create a challenge to clinicians, and every effort should be made to exclude such infections in which community respiratory viruses are isolated. Community respiratory viruses associated with upper respiratory tract infections in patients with hematological malignancies are usually self-limiting and are not associated with increased mortality. However, not uncommonly these patients develop lower respiratory tract infection that is associated with higher mortality [226]. Another potential risk associated with community respiratory viral infections is the development of bronchiolitis obliterans following allogeneic HSCT. In a large series of new-onset airflow obstruction following allogeneic HSCT, one of the main risk factors was respiratory viral infections within the first 100  days following transplantation [233]. Lower respiratory tract parainfluenza [OR 17.9 (95% CI, 2.0–160) and RSV (OR 3.6, 95% CI, 1.0–13)] infections were independent risk factors for development of airflow decline 1 year after allogeneic HSCT [234]. Given the high mortality associated with community respiratory viral lower respiratory tract infections in hematological malignancies, preventive measures play an important role in avoiding infection in these patients. Simple measures such as hand washing are very effective against infection (except for influenza, which is transmitted by aerosolized droplets). In addition, isolating patients suspected to have community respiratory viral infection, even before the infection is confirmed, has been shown to be effective [19]. Symptomatic health-care providers should be restricted from contact with patients with hematological malignancies who are severely immunocompromised [235]. It is also advisable to limit visitors to these patients during the winter months [19].

3.6.1 Respiratory Syncytial Virus (RSV) RSV is one of the most common community respiratory virus infection in patients with hematological malignancies [236–238]. The reported incidence of RSV infection in HSCT recipients ranges between 3.5% and 6.3% and 0.4–1.5% following allogeneic

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and autologous transplantation, respectively [239, 240]. RSV infection usually starts with upper respiratory tract symptoms including cough, rhinorrhea and sinus congestion. Wheezing may develop in 30%; however, fever may not be present even with lower respiratory tract infection [241]. The most serious complication of RSV infection in this patient population is the development of lower respiratory tract infection that happens in up to one third of patients and is associated with high mortality (19%) [226, 242]. Lack of RSV-directed antiviral therapy and older age are associated with increased risk of progression to pneumonia [226]. Other risk factors for RSV pneumonia include male gender, high APACHE II score, protracted lymphopenia and recent corticosteroid therapy [243]. Lower respiratory tract infection is characterized by progressive dyspnea and hypoxemia. The radiological findings of RSV pneumonia include multiple small nodules, bud on tree pattern, diffuse groundglass infiltrates and bronchial thickening [244]. The diagnosis of RSV lower respiratory tract infection could be made by DFA, IFA or PCR of nasopharyngeal or BAL specimens [245]. The role of pharmacological therapy in RSV infection in patients with hematological malignancies remains controversial. Several studies have suggested benefit from ribavirin (intravenously, orally or aerosolized) with or without RSV-specific intravenous immunoglobulins [246, 247]. The efficacy of this treatment once the patient develops acute respiratory failure requiring mechanical ventilation is significantly lower [246]. Delivery of aerosolized ribavirin requires a special machine that is not widely available. Care should be taken during aerosolization of this medication since those who are exposed to it may develop headaches, skin rash and conjunctivitis. Furthermore, ribavirin has teratogenic effects, and pregnant women should not enter the patient’s room during treatment [247]. Other therapeutic modalities, such as high titer monoclonal antibody against RSV, are under investigation [239, 248]. In a recent trial on HSCT, recipients with upper respiratory tract RSV infection were randomized to preemptive aerosolized ribavirin or supportive therapy to prevent progression to lower respiratory tract infection. The intervention was safe and associated with reduced viral load; however, the study could not prove the efficacy of aerosolized ribavirin in preventing progression to lower respiratory tract RSV infection [249].

3  Respiratory Infections in Patients with Hematological Malignancies

3.6.2 Parainfluenza Virus Parainfluenza is another important cause of community respiratory viral infections in patients with hematological malignancies [227, 250, 251]. Parainfluenza has four serotypes, and serotypes 1 and 3 are reportedly the most common causes of infection in these patients. Parainfluenza infection is variable throughout the year, with outbreaks reported in winter, and sometimes in spring and summer. Parainfluenza infection usually presents with cough; however, rhinorrhea and fever are uncommon. Lower respiratory tract infection is the most serious complication of parainfluenza infection and is reported in 18–100% (mean 33%) of patients, with mortality ranging between 15% and 73% (mean 50%) [242]. It is estimated that up to 50% of patients with parainfluenza lower respiratory tract infection have co-infection with bacteria or fungi [251]. The diagnosis of parainfluenza infection is usually made by IFA or DFA and culture of respiratory samples. Real-time PCR is under development and is not available for clinical practice. Treatment of parainfluenza infection is supportive. Ribavirin has activity against parainfluenza and has been shown to be helpful in small studies; [247, 252] however, large studies failed to demonstrate benefit from this therapy [251]. It is recommended to consider aerosolized ribavirin in the treatment of parainfluenza lower respiratory tract infection, although experience to date provides little evidence of efficacy [247].

3.6.3 Influenza Influenza infection has been described in patients with hematological malignancies as a community or nosocomial infection. It develops in the winter months, and the clinical picture is similar to normal hosts with fever, rhinorrhea, coryza, mayalgia and headache. Following HSCT, the frequency of influenza infection is similar with autologous and allogeneic transplantation. In one study of children with cancer, 40% of patients were on chemotherapy, and 63% were lymphopenic. Only one third of the patients were neutropenic [253]. Prognosis is worse in patients with lymphopenia and in those who develop infection early post HSCT [226, 254].

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The treatment of influenza infection is supportive. Antiviral agents, such as amantadine, rimantadine, oseltamivir and zanamivir, may be considered in patients with severe infection [255]. In one report, early treatment with oseltamivir was associated with a trend to less progression to lower respiratory tract infection and decreased viral shedding [254]. Vaccination against influenza is effective; however, live attenuated preparations should be avoided in these patients, and that HSCT recipients may respond poorly to vaccination in the first 2 years following transplantation must be taken into consideration [247]. The pandemic of novel H1N1 influenza is another risk to patients with hematological malignancies. Patients with suspected or confirmed infection should be treated with either oseltamivir or zanamivir. Patients with immunocompromising conditions are advised to receive the inactivated novel H1N1 influenza vaccine [256].

3.6.4 Adenovirus Adenovirus infection accounts for 0–21% of community respiratory viral infections in patients with hematological malignancies and is more common in children [242, 257]. Patients with allogeneic HSCT may have delayed adenovirus-specific T-cell immune recovery, which correlates with increased risk of adenovirus associated morbidity and mortality [258]. App­ roximately 20% of patients with adenovirus infection develop pneumonia [259]. Histologically, the diagnosis is suggested by the presence of the characteristic smudge cells [259]. There are limited antiviral agents with activity against adenovirus. Ribavirin and gancyclovir have no significant activity against this virus [260, 261].

3.6.5 Other Viruses As reported in the paper from Shah and Chemaly, Herpes simplex virus-1 reactivates in the majority of these patients and occasionally may be associated with pneumonia. HHV6 has been suggested to have a role in the pathogenesis of idiopathic pneumonia syndrome following HSCT [262]. It may act as a co-pathogen

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with CMV or as an isolated cause of pneumonia [262]. In a recent report, HHV-6 was isolated from 56.6% of peripheral blood or other specimen tested following HSCT; however, it was associated with interstitial/ alveolar pneumonia in only 2% of patients. HHV-6 reactivation was significantly associated with GVHD, Epstein-Barr viral co-infection, and unrelated donor transplantation [263]. In the chapter from Dr. Schildgen, emerging viral infections are reviewed. Human metapneumovirus is another RNA respiratory virus that has been detected in 3.2% of patients with hematological malignancies. Around half of the patients have pulmonary radiological abnormalities. The prognosis of this infection is good, and the majority of patients do not require antiviral therapy [264].

3.7 Conclusion Patients with hematological malignancies have defects in their immune system that involve one or more of the defense cell lines. These patients are at high risk for a variety of respiratory infectious and noninfectious complications that are related to their underlying malignancies or due to the aggressive therapy of these conditions. There have been significant advances in the diagnosis and management of respiratory infections in patients with hematological malignancies. P. jiroveci and CMV infections are very rare. The treatment of bacterial pneumonias has improved with the availability of broad-spectrum antibiotics. The management of fungal infections, including IPA, is enhanced by the introduction of noninvasive diagnostic methods such as galactomannan assay and better tolerated antifungal agents. Future directions in the management of respiratory infections in patients with hematological malignancies need to focus on more robust and validated noninvasive diagnostic assays that allow for earlier detection and preemptive therapy of fungal and viral infections. Also more emphasis is needed on prevention of respiratory infections. More effective and safer antiviral agents should be another area of research and development as well as the role of combination antimicrobial agents in the management of severe viral and fungal infections. Respiratory infections in patients with hematological malignancies can also be minimized by

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improved treatment regimens including enhanced HSCT techniques that lead to better engraftment and less GVHD. More targeted chemotherapeutic regimens may also decrease the risk of opportunistic infections.

References 1. www.cancer.gov. In: wwwcancergov. Accessed Oct 2009 2. www.ibmtr.org. Accessed Oct 2009 3. Maschmeyer G, Link H, Hiddemann W et  al (1994) Pulmonary infiltrations in febrile patients with neutropenia. Risk factors and outcome under empirical antimicrobial therapy in a randomized multicenter study. Cancer 73(9):2296–2304 4. Soubani AO, Miller KB, Hassoun PM (1996) Pulmonary complications of bone marrow transplantation. Chest 109(4):1066–1077 5. Ewig S, Torres A, Riquelme R et  al (1998) Pulmonary complications in patients with haematological malign­ ancies treated at a respiratory ICU. Eur Respir J 12(1): 116–122 6. Lazarus HM, Vogelsang GB, Rowe JM (1997) Prevention and treatment of acute graft-versus-host disease: the old and the new. A report from the Eastern Cooperative ­Onco­logy Group (ECOG). Bone Marrow Transplant 19(6): 577–600 7. Gerson SL, Talbot GH, Hurwitz S, Strom BL, Lusk EJ, Cassileth PA (1984) Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia. Ann Intern Med 100(3):345–351 8. Hofmeister CC, Czerlanis C, Forsythe S, Stiff PJ (2006) Retrospective utility of bronchoscopy after hematopoietic stem cell transplant. Bone Marrow Transplant 38(10): 693–698 9. Paulin T, Ringden O, Lonnqvist B (1985) Faster immunological recovery after bone marrow transplantation in patients without cytomegalovirus infection. Transplantation 39(4):377–384 10. Witherspoon RP, Storb R, Ochs HD et al (1981) Recovery of antibody production in human allogeneic marrow graft recipients: influence of time posttransplantation, the presence or absence of chronic graft-versus-host disease, and antithymocyte globulin treatment. Blood 58(2):360–368 11. Aucouturier P, Barra A, Intrator L et al (1987) Long lasting IgG subclass and antibacterial polysaccharide antibody deficiency after allogeneic bone marrow transplantation. Blood 70(3):779–785 12. Kotloff RM, Ahya VN, Crawford SW (2004) Pulmonary complications of solid organ and hematopoietic stem cell transplantation. Am J Respir Crit Care Med 170(1): 22–48 13. Sloane JP, Depledge MH, Powles RL, Morgenstern GR, Trickey BS, Dady PJ (1983) Histopathology of the lung after bone marrow transplantation. J Clin Pathol 36(5):546–554

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217. Nichols WG, Price TH, Gooley T, Corey L, Boeckh M (2003) Transfusion-transmitted cytomegalovirus infection after receipt of leukoreduced blood products. Blood 101(10):4195–4200 218. Zaia JA (1993) Prevention and treatment of cytomegalovirus pneumonia in transplant recipients. Clin Infect Dis 17(Suppl 2):S392–S399 219. Goodrich JM, Bowden RA, Fisher L, Keller C, Schoch G, Meyers JD (1993) Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant. Ann Intern Med 118(3):173–178 220. Busca A, de Fabritiis P, Ghisetti V et al (2007) Oral valganciclovir as preemptive therapy for cytomegalovirus infection post allogeneic stem cell transplantation. Transpl Infect Dis 9(2):102–107 221. Lilleri D, Gerna G, Furione M, et  al (2007) Use of a DNAemia cut-off for monitoring human cytomegalovirus infection reduces the number of pre-emptively treated children and young adults receiving haematopoietic stem cell transplantation as compared to qualitative pp65-antigenemia. Blood 222. Walter EA, Greenberg PD, Gilbert MJ et  al (1995) Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 333(16): 1038–1044 223. Lujan-Zilbermann J, Benaim E, Tong X, Srivastava DK, Patrick CC, DeVincenzo JP (2001) Respiratory virus infections in pediatric hematopoietic stem cell transplantation. Clin Infect Dis 33(7):962–968 224. Roghmann M, Ball K, Erdman D, Lovchik J, Anderson LJ, Edelman R (2003) Active surveillance for respiratory virus infections in adults who have undergone bone marrow and peripheral blood stem cell transplantation. Bone Marrow Transplant 32(11):1085–1088 225. van Kraaij MG, van Elden LJ, van Loon AM et al (2005) Frequent detection of respiratory viruses in adult recipients of stem cell transplants with the use of real-time polymerase chain reaction, compared with viral culture. Clin Infect Dis 40(5):662–669 226. Chemaly RF, Ghosh S, Bodey GP et al (2006) Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center. Medicine (Baltimore) 85(5):278–287 227. Bowden RA (1997) Respiratory virus infections after marrow transplant: the Fred Hutchinson Cancer Research Center experience. Am J Med 102(3A):27–30, discussion 42-3 228. Franquet T, Rodriguez S, Martino R, Gimenez A, Salinas T, Hidalgo A (2006) Thin-section CT findings in hematopoietic stem cell transplantation recipients with respiratory virus pneumonia. AJR Am J Roentgenol 187(4): 1085–1090 229. Whimbey E, Englund JA, Couch RB (1997) Community respiratory virus infections in immunocompromised patients with cancer. Am J Med 102(3A):10–18, discus­sion 25-6 230. Raboni SM, Nogueira MB, Tsuchiya LR et  al (2003) Respiratory tract viral infections in bone marrow transplant patients. Transplantation 76(1):142–146 231. Bredius RG, Templeton KE, Scheltinga SA, Claas EC, Kroes AC, Vossen JM (2004) Prospective study of respira-

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Part Epidemiology

II

 

4

Epidemiology of Respiratory Events in Patients with HM (Not Including ICU) Georg Maschmeyer

Contents 4.1

Respiratory Events in Patients with Hematological Malignancies.................................. 41

4.2

Lung Infiltrates in Patients with HM.................... 42

4.3

Acute Respiratory Failure in Cancer Patients................................................... 43

References............................................................................ 44

G. Maschmeyer  Department of Hematology, Oncology and Palliative Care, Center for Hematology, Oncology and Radiotherapy, Klinikum Ernst von Bergmann, Charlottenstr. 72, D-14467 Potsdam, Germany e-mail: [email protected]

4.1 Respiratory Events in Patients with Hematological Malignancies Respiratory events, defined as episodes of respiratory symptoms or signs, such as dyspnea, cough, sputum, chest pain, rales, hemoptysis, oxygenation impairment or pulmonary infiltrates on chest radiograph or computed tomography scan, are frequent among patients with hematological malignancies (HM). Almost 50% of patients with acute leukemia undergoing chemotherapy may be affected [10], preferably those with preexisting pulmonary disease and smokers. Also among patients with chronic lymphocytic leukemia, respiratory events are frequent and are likely to take a complicated course caused by the complex immunodeficiency in these patients. Pulmonary events have been reported for up to 58% of patients with malignant lymphoma undergoing high-dose chemotherapy and autologous hematopoietic stem cell transplantation [18], but in general, less than 10% of all autologous stem cell transplant patients will develop pneumonia [27, 30]. The epidemiology of respiratory events has only rarely been investigated using invasive procedures, so that reliable data on specific causes in different subgroups of patients with HM are sparse. Chaoui et al. investigated consecutive patients with newly diagnosed acute leukemia over 1 year to evaluate the incidence and prognostic value of these events and found that the cause of respiratory events was infectious in 34% of cases, an established cause other than infection in 42% and an undetermined cause in 24%. Among patients with undetermined etiology, around 20% were cured by antibiotics and could be considered as probable bacterial pneumonia, increasing the proportion of infectious causes to 55%. Aspergillosis was proven in approximately 10% of cases. The majority of

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_4, © Springer-Verlag Berlin Heidelberg 2011

41

42

respiratory events occurred after starting induction chemotherapy; however, almost all respiratory events of undetermined etiology were present at diagnosis of HM already, and respiratory events of non-infectious origin typically occurred within 10 days of leukemia diagnosis. Among patients with chronic lymphocytic leukemia, pulmonary complications analyzed over a 9-year period were associated with a poor prognosis and a fatality rate of 40% [1]. Notably, 25% of these complications were not caused by pneumonia, but by pleural effusion or lung infiltration by the underlying malignancy (9%), pulmonary leukostasis (4%), secondary malignancies or Richter’s syndrome (3%), or bronchial obstruction (2%). With respect to prognosis, granulocytopenia and renal failure had an unfavorable impact on clinical outcome.

G. Maschmeyer Table 4.1  Drugs potentially associated with pulmonary toxicity in patients with hematological malignancies Alkylating agents   Busulfan   Chlorambucil   Cyclophosphamide Antimetabolites   Azathioprine   Cytosine arabinoside   Fludarabine   Gemcitabine   Methotrexate Cytotoxic antibiotics   Bleomycin   Dactinomycin   Doxorubicin

4.2 Lung Infiltrates in Patients with HM

  Mitomycin Nitrosoureas

In febrile neutropenic patients, lung infiltrates emerge in up to 30% [31]. Clinical outcome deteriorates with increasing patient age, and is particularly dismal in patients with bacteremia and shock as well as in case of delayed appropriate antimicrobial treatment [7, 21]. Infiltrates become apparent in approximately two thirds of cases within 5 days after the onset of fever. As compared with other types of infections, lung infiltrates in neutropenic patients are associated with a higher risk of mortality [3, 15, 26], and their treatment is more difficult and costly [19]. Histopathological findings show that these infiltrates may have numerous different causes, including multi-resistant bacteria [32] and pathogens not susceptible to beta-lactam antibiotics [20], alveolar bleeding, infiltration by the underlying malignancy, cryptogenic organizing pneumonia, immune reconstitution syndrome, and lesions caused by chemotherapy or radiation [2, 4, 8, 13, 14, 35, 36], In particular, the differential diagnosis of drug-induced lung infiltrates should be kept in mind (Table 4.1). Successful clinical response to broad-spectrum antibacterial treatment is observed in less than 30% of patients with pulmonary infiltrates in the course of febrile neutropenia [26, 29], whereas prompt addition of mold-active systemic antifungals increases the response rate to up to 78% [34]. The dramatic

  BCNU (carmustine)   CCNU (lomustine) Assorted agents   Procarbazine   Sirolimus   Taxanes   Vinca alkaloids Modified after Shorr et al. [36]

reduction of lung infiltrates in acute leukemia patients under voriconazole prophylaxis [38], along with histopathological and molecular [20] as well as autopsy studies [4, 9, 17], indicate that the majority of those infiltrates are caused by filamentous fungi, particularly by Aspergillus spp. Clinical outcome of microbiologically or histologically documented invasive aspergillosis in neutropenic patients is poor [12, 22, 28], so that early pre-emptive antifungal treatment is recommended in febrile patients with severe neutropenia and pulmonary infiltrates whose radiological morphology is not typical for non-fungal origin [24, 39]. This recommendation also takes into account that Aspergillus pneumonia will have an unfavorable impact on longterm prognosis and that early institution of systemic

4  Epidemiology of Respiratory Events in Patients with HM (Not Including ICU)

antifungal treatment against Aspergillus spp. improves survival [5, 34]. In patients treated with nucleoside analog, microorganisms typically observed under prolonged cellular immunosuppression, such as cytomegalovirus, mycobacteria or yeasts, must be considered [33], as well as Staphylococcus aureus, Pseudomonas aeruginosa, Aspergillus spp. and pneumococci [1]. Respiratory viruses such as Influenza A or Respiratory Syncytial Virus have occasionally been identified as causes of pulmonary infiltrates in hospitalized, febrile neutropenic patients [23, 37], predominantly during wintertime, but they do not occur more frequently in immunocompromised than in non-immunocompromised patients [16]. Among patients affected, those who are older than 65 years of age or have severe lymphocytopenia may show a mortality rate of 5–15% [11].

43

4.3 Acute Respiratory Failure in Cancer Patients [3] performed a prospective 5-year observational study in a medical intensive care unit treating 203 cancer patients with acute respiratory failure and reported that repiratory failure was mainly due to infectious pneumonia (58%), but also due to lung inflammation due to non-infectious causes in 9% and to congestive heart failure in 12% of patients, whereas no cause was identifiable in 21%. Mortality of HM patients with respiratory events requiring referral to an intensive care unit is high, though decreases over time [10]. Half the patients do not survive their respiratory events (Fig.  4.1). Multivariate analysis shows the type and state of the underlying malignancy [3], proven pulmonary aspergillosis, the

65 patients

30 RE (46%)

35 no RE

Acute respiratory failure 20/30 patients (66%)

Intensive care 12/20 patients

Remain in hematology 8/20 patients

Return to hematology 5/12 patients

Fig. 4.1  Outcome of acute leukemia patients with respiratory events (RE) (end point: death within 45 days of the start of induction chemotherapy) (From [10])

Death in intensive care 7/12 patients

Death in hematology department 9/13 patients

Death from disease progression in hematology department 2 patients

44

G. Maschmeyer

Table 4.2  Multivariable analysis: independent predictors of hospital death in cancer patients with acute respiratory failurea Odds ratio 95% Confidence p Value interval Cause of ARF Congestive heart failure

0.16

0.03–0.72

0.01

Invasive aspergillosis

3.78

1.05–14.24

0.049

No definite diagnosis

3.85

1.26–11.70

0.01

Need for vasopressors

3.19

1.28–7.95

0.01

NIMV only

1.58

0.37–6.70

0.52

NIMV followed by conventional MV

17.46

5.04–60.52

<0.0001

First-line conventional MV

8.75

2.35–32.54

0.001

Late NIMV failureb

10.64

1.05–107.83

0.04

Need for respiratory support

Hosmer–Lemeshow chi-square p value = 0.78 Late NIMV failure: need for conventional MV after 2 full days of NIMV From Azoulay et al. [3] a

b

lack of a definite diagnosis, the need for pressor support and the requirement of invasive mechanical ventilation after failure of non-invasive ventilation as independent poor-risk factors (Table 4.2); however, the prognosis is not unequivocally dismal. In a long-term analysis, it has been demonstrated that at least three unfavorable factors had to be present to clearly predict fatal outcome [25], so that intensive care should be offered to all patients who do not have an unequivocally fatal prognosis. In this book, two papers are dedicated to patient outcome. Dr. Groeger and Dr. Azoulay provide an up-to-date literature analysis, as well as an appraisal of determinants of the outcomes in hematological patients requiring ICU management.

References   1. Ahmed S, Siddiqui AK, Rossoff L, Sison CP, Rai KR (2003) Pulmonary complications in chronic lymphocytic leukemia. Cancer 98:1912–1917   2. Azoulay E, Darmon M, Delclaux C et al (2002) Deterioration of previous acute lung injury during neutropenia recovery. Crit Care Med 30:781–786   3. Azoulay E, Thiery G, Chevret S et al (2004) The prognosis of acute respiratory failure in critically ill cancer patients. Medicine (Baltimore) 83:360–370   4. Bodey G, Bueltmann B, Duguid W et  al (1992) Fungal infections in cancer patients: an international autopsy survey. Eur J Clin Microbiol Infect Dis 11:99–109

  5. Caillot D, Casasnovas O, Bernard A et al (1997) Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery. J Clin Oncol 15:139–147   6. Camus P, Costabel U (2005) Drug-induced respiratory disease in patients with hematological diseases. Semin Respir Crit Care Med 26:458–81   7. Carratalà J, Rosón B, Fernández-Sevilla A, Alcaide F, Gudiol F (1998) Bacteremic pneumonia in neutropenic patients with cancer: causes, empirical antibiotic therapy, and outcome. Arch Intern Med 158:868–872   8. Cazzadori A, di Perri G, Todeschini G et  al (1995) Transbronchial biopsy in the diagnosis of pulmonary infiltrates in immunocompromised patients. Chest 107:101–106   9. Chamilos G, Luna M, Lewis RE et al (2006) Invasive fungal infections in patients with hematologic malignancies in a tertiary care cancer center: an autopsy study over a 15-year period (1989-2003). Haematologica 91:986–989 10. Chaoui D, Legrand O, Roche N et al (2004) Incidence and prognostic value of respiratory events in acute leukemia. Leukemia 18:670–675 11. Chemaly RF, Torres HA, Aguilera EA et  al (2007) Neuraminidase inhibitors improve outcome of patients with leukemia and influenza: an observational study. Clin Infect Dis 44:964–967 12. Cornillet A, Camus C, Nimubona S et al (2006) Comparison of epidemiological, clinical, and biological features of invasive aspergillosis in neutropenic and nonneutropenic patients: a 6-year survey. Clin Infect Dis 43:577–584 13. Danés C, Gonzalez-Martin J, Pumarola T et  al (2002) Pulmonary infiltrates in immunosuppressed patients: analysis of a diagnostic protocol. J Clin Microbiol 40: 2134–2140 14. Daniels CE, Myers JL, Utz JP, Markovic SN, Ryu JH (2007) Organizing pneumonia in patients with hematologic

4  Epidemiology of Respiratory Events in Patients with HM (Not Including ICU) malignancies: a steroid-responsive lesion. Respir Med 101: 162–168 15. Ewig S, Glasmacher A, Ulrich B et  al (1998) Pulmonary infiltrates in neutropenic patients with acute leukemia during chemotherapy. Chest 114:444–451 16. Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE (2005) Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med 352:1749–1759 17. Groll AH, Shah PM, Mentzel C, Schneider M, Just-Nuebling G, Huebner K (1996) Trends in the postmortem epidemiology of invasive fungal infections at a university hospital. J Infect 33:23–32 18. Jules-Elysee K, Stover DE, Yahalom J, White DA, Gulati SC (1992) Pulmonary complications in lymphoma patients treated with high-dose therapy autologous bone marrow transplantation. Am Rev Respir Dis 146:485–491 19. Kuderer NM, Dale DC, Crawford J, Cosler LE, Lyman GH (2006) Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer 106: 2258–2266 20. Lass-Flörl C, Resch G, Nachbaur D (2007) The value of computed tomography-guided percutaneous lung biopsy for diagnosis of invasive fungal infection in immunocompromised patients. Clin Infect Dis 45:e101–e104 21. Lin MY, Weinstein RA, Hota B (2008) Delay of active antimicrobial therapy and mortality among patients with bacteremia: impact of severe neutropenia. Antimicrob Agents Chemother 52:3188–3194 22. Lin SJ, Schranz J, Teutsch SM (2001) Aspergillosis casefatality rate: systematic review of the literature. Clin Infect Dis 32:358–366 23. Martino R, Ramila E, Rabella N et  al (2003) Respiratory virus infections in adults with hematologic malignancies: a prospective study. Clin Infect Dis 36:1–8 24. Maschmeyer G, Beinert T, Buchheidt D et  al (2009) Diagnosis and antimicrobial therapy of pulmonary infiltrates in febrile neutropenic patients. 2008 updated guidelines of the Infectious Diseases Working Party of the German Society of Hematology and Oncology. Eur J Cancer 45:2462–2472 25. Maschmeyer G, Bertschat FL, Häusler E et  al (2003) Outcome analysis of 189 consecutive cancer patients referred to the intensive care unit as emergencies during a 2-year period. Eur J Cancer 39:783–792 26. Maschmeyer G, Link H, Hiddemann W et  al (1994) Pulmonary infiltrations in febrile neutropenic patients. Risk factors and outcome under empirical antimicrobial therapy in a randomized multicenter trial. Cancer 73:2296–2304 27. Mossad SB, Longworth DL, Goormastic M, Serkey JM, Keys TF, Bolwell BJ (1996) Early infectious complications

45

in autologous bone marrow transplantation: a review of 219 patients. Bone Marrow Transplant 18:265–271 28. Pagano L, Caira M, Candoni A et al (2006) The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica 91: 1068–1075 29. Raad II, Whimbey EE, Rolston KVI et al (1996) A comparison of aztreonam plus vancomycin and imipenem plus vancomycin as initial therapy for febrile neutropenic cancer patients. Cancer 77:1386–1394 30. Reich G, Mapara MY, Reichardt P, Dörken B, Maschmeyer G (2001) Infectious complications after high-dose chemotherapy and autologous stem cell transplantation: comparison between patients with lymphoma or multiple myeloma and patients with solid tumors. Bone Marrow Transplant 27:525–529 31. Rossini F, Verga M, Pioltelli P et  al (2000) Incidence and outcome of pneumonia in patients with acute leukemia receiving first induction therapy with anthracycline-containing regimens. Haematologica 85:1255–1260 32. Safdar A, Rolston KV (2007) Stenotrophomonas maltophilia: changing spectrum of a serious bacterial pathogen in patients with cancer. Clin Infect Dis 45:1602–1609 33. Samonis G, Kontoyiannis DP (2001) Infectious complications of purine analog therapy. Curr Opin Infect Dis 14: 409–413 34. Schiel X, Link H, Maschmeyer G (2006) A prospective, randomized multicenter trial of the empirical addition of antifungal therapy for febrile neutropenic cancer patients. Infection 34:118–126 35. Shorr AF, Susla GM, O’Grady NP (2004) Pulmonary infiltrates in the non-HIV-infected immunocompromised patient: etiologies, diagnostic strategies, and outcomes. Chest 125:260–271 36. Suzuki HI, Asai T, Tamaki Z, Hangaishi A, Chiba S, Kurokawa M (2008) Drug-induced hypersensitivity syndrome with rapid hematopoietic reconstitution during treatment for acute myeloid leukemia. Haematologica 93: 469–470 37. Torres HA, Aguilera EA, Mattiuzzi GN et  al (2007) Characteristics and outcome of Respiratory Syncytial Virus infection in patients with leukemia. Haematologica 92:1216–1223 38. Vehreschild JJ, Böhme A, Buchheidt D et al (2007) A double-blind trial on prophylactic voriconazole or placebo during induction chemotherapy for acute myelogenous leukaemia. J Infect 55:445–449 39. Walsh TJ, Anaissie EJ, Denning DW et al (2008) Treatment of aspergillosis: clinical practice guidelines of the Infecti­ ous Diseases Society of America. Clin Infect Dis 46: 327–360

 

5

Epidemiology of Acute Respiratory Failure in Patients with HM (ICU Only) Carlos Agustí, Carmen Lucena, and Antoni Torres

Contents

5.1 Introduction

5.1 Introduction............................................................. 47 5.2 Main Indications for ICU Admission.................... 48 5.3 Etiology of Pulmonary Infections.......................... 5.3.1 Bacterial Infections................................................... 5.3.2 Invasive Fungal Infections........................................ 5.3.3 Cytomegalovirus (CMV).......................................... 5.3.4 Respiratory Viruses...................................................

48 48 49 49 49

5.4 Survival in the ICU................................................. 5.4.1 Selection of Patients................................................. 5.4.2 Transplant Specific Factors....................................... 5.4.3 Ventilatory Support................................................... 5.4.4 Importance of Establishing a Specific Diagnosis..... 5.4.5 Other Factors Influencing Survival...........................

50 51 51 51 52 53

5.5 Conclusions.............................................................. 53 References............................................................................ 54

C. Agustí () Pneumology Department, Clinic Institute of Thorax (ICT), Hospital Clinic of Barcelona – Insitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Ciber de Enfermedades Respiratorias, University of Barcelona (UB), Villarroel 170, 08036 Barcelona, Spain e-mail: [email protected] C. Lucena and A. Torres Pneumology Department, Clinic Institute of Thorax (ICT), Hospital Clinic of Barcelona – Insitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Villarroel 170, 08036 Barcelona, Spain and Beca Josep Font. Hospital Clínic de Barcelona, Barcelona, Spain e-mail: [email protected]

Great progress has been made in stem cell transplantation over the last years. Most of the progress can be ascribed to an understanding of the human leukocyte antigen (HLA) system for donor selection, immunosuppression for prevention and treatment of graftversus host disease (GVHD), and significant advances in infectious disease prevention, therapy and supportive care. As a result of this progress, the number of potential candidates to receive a transplant has greatly increased, and the survival figures have been progressively encouraging. In fact, the term “hematopoietic stem cell transplantation” (HSCT) has supplanted the previously employed term “bone marrow transplantation” to reflect the broader range of donor stem cell sources available: bone marrow, fetal cord blood, and growth factor-stimulated peripheral blood [1]. Unfortunately, the use of aggressive chemotherapeutic regimens frequently results in life-threatening complications, requiring transfer to the intensive care unit (ICU). Pulmonary complications, both infectious and noninfectious, occur in up to 60% of HSCT recipients, and a significant percentage of them will require ICU admission [1–3]. Infectious complications are more common in allograft recipients because of the requirement of immunosuppressive agents to prevent and treat GVHD. In addition, GVHD itself causes an immunodeficient state. In contrast, noninfectious acute lung injury syndromes (e.g., idiopathic pneumonia syndrome, diffuse alveolar hemorrhage) occur after

Supported by: 2009 SGR 911, Ciber de Enfermedades Res­piratorias (Ciberes CB06/06/0028), el Ciberes es una iniciativa del ISCIII.

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_5, © Springer-Verlag Berlin Heidelberg 2011

47

48

both allogeneic and autologous transplantation with similar frequency [1]. The recognition as well as management of pulmonary complications that result from immunosuppression is a challenging task for clinicians. Although the above-described improvements in patient care have improved the overall survival, once a patient with a hematologic malignancy requires advanced intensive care support, the prognosis worsens significantly with high associated mortality rates, particularly in patients with acute respiratory failure (ARF). Although the survival rate of HSCT recipients admitted to the ICU has been steadily improving, it remains under 50%, with a long-term survival rate under 20% [4].

5.2 Main Indications for ICU Admission It is estimated that 15–30% of the HSCT recipients are admitted to the medical ICU for the management of different complications, with 20% of them requiring mechanical ventilation (MV). In our experience from data collected within a 10-year period [5], 89 patients with hematological malignancies with pulmonary complications were admitted to a respiratory ICU. Fifty-two of 89 (58%) of these patients were HSCT recipients. Patients were admitted to the ICU because of ARF in 61 instances (68%; including 23 patients with acute respiratory distress syndrome, ARDS), sepsis syndrome (12%), pulmonary hemorrhage (9%), heart failure (8%), and miscellaneous conditions (2%). The most common cause of ARF was a pulmonary infection, which was diagnosed in 60% of the patients for whom a specific diagnosis was obtained. Other authors have also found that infection is the most frequent cause of admission to the ICU, particularly in those with neutropenia where up to 80% have a clinically documented infection [6–8]. Also, among organ failures at ICU admission, acute respiratory failure and severe sepsis or septic shock are present in up to 80% of critically ill cancer patients [2, 9] (Table 5.1). Clinical management of infections in critically ill immunocompromised patients is complex since virtually any microorganism may be involved at any time in the evolution, mainly depending on the net state of immunosuppression. The high associated mortality requires a rapid and sometimes invasive diagnostic approach to trying to obtain an etiological diagnosis allowing the early introduction of specific treatment.

C. Agustí et al. Table 5.1  Indications by organ system for ICU admission Respiratory

48%

Sepsis

23%

Cardiac

19%

Neurologic

6%

Bleeding

2%

Others

2%

Modified from ref. [10]

5.3 Etiology of Pulmonary Infections 5.3.1 Bacterial Infections Bacteria are the most frequent cause of pulmonary infections in patients with hematological malignances, accounting for 15–20% of all respiratory infections in HSCT recipients [1] with an associated mortality of 22% [10] (Table 5.2). Different series have shown that bacterial pneumonia is also the most common cause of admission to the ICU in HSCT recipients [11]. One of the problems in diagnosing bacterial pneumonia in hematological patients is the inability to identify the organism in the majority of these patients, which may underestimate the incidence of these infections. Factors that generally increase the risk of bacterial pneumonia following HSCT include pre-transplantation immune status, type of conditioning regimen, and degree and duration of neutropenia [12]. In transplant recipients, bacterial infections may occur at any time in the postTable  5.2  Etiologic diagnosis in HSCT recipients and in haematological patients HSCT Hematologic recipients (%) patients (%) Bacterial

11

23

Fungal

13

19

Polymicrobial

20

8

Other infections

2

4

Pulmonary edema

5

4

DAH

8

4

NOC

3

4

Other non-infections etiologies

7

6

Undetermined

23

28

Modified from ref. [7]

5  Epidemiology of Acute Respiratory Failure in Patients with HM (ICU Only)

transplantation period; however, they seem to be more common in the pre-engraftment phase due to the presence of mucositis and neutropenia. Potential pathogens are myriad. Encapsulated organisms, such as Streptococcus pneumoniae and Haemophilus influenzae, are particularly prevalent; however, many other bacteria must also be considered, particularly Staphyloccocus aureus (including methicillin-resistant, MRSA) and multi-resistant gram-negative bacilli, such as P. aeruginosa [13]. Some epidemiological studies have shown that Legionella sp. pneumonia is more prevalent in the immunocompromised host [14]. It is important to consider that 15–30% of cases ­diagnosed as bacterial pneumonia are mixed ­bacterial/opportunistic infections [11–13]. This fact has to be considered, particularly in patients that do not respond to appropriate specific antibiotic treatment.

49

With regard to Candida infections, with the expanded use of the new antifungal therapies, a higher incidence of infections caused by Candida kruseii and Candida glabrata has been reported [17, 18]. Also infections due to fusarium, Penicillium purpurogenum [19], and Scedosporium prolificans [20, 21] are increasingly being reported. In contrast, a marked decrease in the incidence of P. jiroveci pneumonia has been observed over the last years, mainly because of prescription of specific prophylaxis in patients at risk [22]. In a recent report, P. jiroveci infection was documented in 2.5% of patients undergoing allogeneic HSCT (2.5%). The majority of cases occurred late in the course following HSCT (median 14.5 months) [23] and with a CD4+ count less than 200 cells/mm3.

5.3.3 Cytomegalovirus (CMV) 5.3.2 Invasive Fungal Infections Since neutrophils are the key cells in the defense against aspergillus sp. and other molds, the neutropenic patient and particularly HSCT recipients are at highest risk for dissemination. A steady rise in the documented cases of invasive pulmonary aspergillosis (IPA) post-transplantation has been documented. The risk for IPA is much higher following allogeneic HSCT when compared to autologous transplantation (incidence is 2.3–15% and 0.5–4%, respectively) [15]. Mortality rates for HSCT recipients with IPA have historically been as high as 80%; however, during the past 2 decades, the outcome of this infection seems to be changing. Recently, the Prospective Antifungal Therapy Alliance Registry performed a multicenter study to assess the epidemiology and outcomes of invasive fungal infections in HSCT recipients [16]. In this study, a total of 250 proven or probable invasive fungal infections were included. Almost 70% of the patients had received an allogeneic HSCT, and 31% had received an autologous HSCT. In this series, mortality rates of 21% and 35% at 6 and 12 weeks of diagnosing proven or probable IPA were reported, numbers that are consistent with those reported by other authors, confirming the survival gain evidenced after the inclusion of azoles in the therapeutic armamentarium of invasive fungal infections. Interestingly, the absence of MV or/and hemodialysis was significantly associated with improved survival.

Traditionally, CMV pneumonia has affected 20–35% of HSCT recipients [24], being a common cause of ICU admission. However, the application of antiviral prophylaxis and the systematic use of preemptive therapy have changed the epidemiology of CMV pneumonia in HSCT recipients. Currently, in allogeneic HSCT recipients, the incidence of CMV pneumonia is 10–30% [25]. Also mortality is revised downwards between 30% and 50%. In the pre-prophylaxis era, onset of CMV pneumonia almost invariably occurred between engraftment and day 100. The use of prophylaxis has also shifted the onset of CMV pneumonia in allogeneic HSCT to after the first 100 days, especially in patients with non-myeloablative HSCT and during the treatment of chronic GVHD [26]. Despite improvements in specific treatment, survival of patients with established respiratory failure requiring mechanical ventilation is very poor.

5.3.4 Respiratory Viruses Recent developments in molecular-based diagnostic tools have shown that conventional respiratory viruses [influenza, parainfluenza, respiratory syncitial viruses (RSV), adenoviruses, enteroviruses, and rhinoviruses] may commonly cause respiratory illnesses with significant morbidity and mortality among HSCT recipients. The incidence of these

50

viral infections following HSCT ranges between 11–65% [27]. Upper respiratory tract infections in HSCT recipients are usually self-limiting. However, the progression to pneumonia carries a significant associated mortality. In one study of community respiratory viral infections following HSCT, the main viruses were RSV (35%), parainfluenza (30%), rhinovirus (25%), and influenza virus (11%). Of these, pneumonia occurred in 49% of patients with RSV infection, 22% of those with parainfluenza virus, and 3% of rhinovirus infection [28]. In another recent review of 343 cases of community respiratory viral infections in 306 adults with hema­tological malignancies (mostly HSCT recipients), parainfluenza (mainly type 3) accounted for 27% of infections, influenza (mainly type A) for 33% of infections, and RSV for 31% of infections. Community respiratory viral infections progressed to pneumonia in 35% of patients with equal frequency among the three viruses [27]. Interestingly, community respiratory viruses are often co-pathogens with other organisms, including bacteria, fungi (aspergillus), or other viruses (CMV). Herpes simplex virus 1 reactivates in 80% of HSCT recipients and occasionally may be associated with pneumonia. However, universal prophylaxis with acyclovir and gancyclovir has significantly reduced the incidence [27, 29]. Human herpes virus (HHV-6) may act as a co-pathogen with CMV or act as an isolated cause of pneumonia [30].

5.4 Survival in the ICU In this book, Groeger and colleagues report updated data on outcomes in patients with hematological malignancies admitted to the ICU. Suffering from hematologic malignances is one of the most powerful predictors of mortality due to ARF in the ICU, and this is particularly true when patients with HSCT are considered and when MV is required. For many years, survival was considered dismal, with physicians supporting either denial of ICU admission or considering early treatment limitation decisions. Shuster and Marion [31] found a mortality of 80% in 77 patients treated in the ICU. Our study, evaluating prognostic factors of non-HIV-positive immunocompromised patients with pulmonary complications, showed that

C. Agustí et al.

the mortality rate among HSCT recipients was almost twofold higher than that of patients with hematological malignances or of those who had received solid organ transplants. The requirement of mechanical ventilation was a critical predictor of poor outcome with mortality rates approaching 95% [7]. Long-term survival rates after MV are also dismal in recipients of allogeneic HSCT with active GVHD, with approximately 5% of patients surviving 6 months. Consequently, some clinicians have questioned the utilization of mechanical ventilatory support for these patients. Over the last years, the pessimistic vision of the dismal outcome of hematological patients admitted to the ICU seems to be changing. First, the number of hematological patients requiring further ICU admission or MV has been decreasing [9]. Second, recent series support the notion that the prognosis for hematological patients admitted to the ICU has improved compared to that reported in the 1980s and early 1990s [32, 33]. Benoit et al. [32], evaluating a cohort of 124 patients with a hematologic malignancy admitted to the ICU for a life-threatening complication, observed an ICU and in-hospital mortality of 42% and 54%, respectively. Soubani et  al. [2] evaluated 85 patients admitted to the medical ICU, representing 11.4% of patients who had undergone HSCT during the study period. Fifty-two patients (61%) survived their ICU stay, and 35 patients (41%) were discharged alive from the hospital. The long-term survival rate (>6 months) in this cohort was 28%. Moreover, 19 patients receiving MV (37%) survived their ICU stay, and 33 (97%) patients who did not require MV survived. The study showed short-term and long-term survival rates among adult HSCT recipients who had been admitted to the ICU that were higher than those previously reported. Azoulay et al. [34], in a study evaluating a large group of cancer patients with ARF due to a variety of causes, reported a mortality rate of less than 50%, reaffirming the survival gains achieved in critically ill cancer patients in recent years. Although the above-mentioned results are promising, some factors should lead us to temper this optimistic picture. A recent meta-analysis by Van Gestel et al. [35] in a population of children did not show survival improvement over time when the variable MV was considered. When the specific studies included in this meta-analysis were individually evaluated, it was shown that some of them showed improved survival in

5  Epidemiology of Acute Respiratory Failure in Patients with HM (ICU Only)

ventilated, post-HSCT patients, while others did not show such improvement. Even in those studies that reported improved survival, the need for MV was a strong indicator of worse prognosis. These controversial results may be due to many different variables accounting for survival in hematological patients requiring ICU admission. In the following, we report some of the most determining variables that have been related to survival in HSCT recipients.

51

The number of HSCT recipients requiring ICU admission is decreasing [2]. This lower ratio of admissions is unlikely to be due to the underutilization of ICU resources. Rather, it is probably related to a shorter neutropenic phase, better antimicrobial prophylaxis and treatment, and improved experience in the management of these patients before their condition deteriorates. Also, the improved survival may partially be explained by the implantation of restrictive policies for selecting patients to ICU admission. Although the selection of the best candidates for ICU care is difficult and there are no objective data to support the decision [36], it is possible that selection of patients who are most likely to benefit from ICU admission might explain part of the survival gains. Also, it is possible that the decrease in mortality was, in fact, accompanied by a decrease in the number of patients requiring MV, a known risk factor for poor outcome. Reasons for a decrease in the number of HSCT patients who require MV may be related to a decrease in pulmonary complications in these patients or because hematologists and intensivists are better at the early management of pulmonary complications, thereby minimizing the number of patients who ultimately require MV [3, 37].

administration of immunosuppressive agents after transplantation to prevent or treat GVHD. In addition, GVHD itself causes an immunodeficient state by involving mucosal surfaces, the reticuloendothelial system, and bone marrow. Because of all this, the mortality of recipients of allogeneic HSCT, requiring lifesustaining measures, is extremely high [3, 9]. In contrast, autologous HSCT recipients, who receive a less intense conditioning regimen, have a similar prognosis to other critically ill cancer patients in that their short-term risk of death depends only on the number and type of organ dysfunctions. Few studies have emphasized the radically different outcomes between allogeneic and autologous HSCT recipients in the ICU. Shorr et al. [38] collected data focusing only on autologous HSCT, with the aim of determining the frequency of and risk factors for the use of MV in this population. These authors concluded that MV is infrequently needed following autotransplants. Of 159 patients included, only 17 required MV (10.7%), with 3 of them surviving the episode (17.6%). It is possible that the large proportion of autologous transplantation recipients included in the recently published cohorts might be a confounding factor and led to an underestimation of the mortality rate of allogeneic graft recipients. In particular, the recent series by Soubani et al. [2], which showed a significant improvement in survival in HSCT recipients, included a cohort with almost half of the patients (47%) having received an autologous HSC transplant. Finally, other reasons related to the transplantation technique that can indicate an improved survival are the reduced toxicity of conditioning regimens, the use of alternative hematopoietic precursor sources, such as mobilized peripheral blood stem cells, and cytokines, such as hematopoietic cell colony-stimulating factors, which significantly shorten the time to engraftment, thus decreasing the incidence of infectious pulmonary complications.

5.4.2 Transplant Specific Factors

5.4.3 Ventilatory Support

HSCT recipients have “per se” an adverse prognostic factor in many studies. However the prognosis of both autologous and allogeneic HCT seems to be different. In allogeneic HSCT recipients, infectious complications are more common because they require the

The outcome of alo-HSCT recipients requiring MV has not improved for 2 decades, with consistent survival rates of less than 20% [37, 39, 40] Patients requiring MV have a worse prognosis than similar patients matched for general severity-of-illness

5.4.1 Selection of Patients

52

C. Agustí et al.

scoring systems such as APACHE II, because MV may be directly injurious through increasing the risk for nosocomial pneumonia [41, 42]. Moreover, the association of ARF requiring MV with other organ failures has been reported to be almost uniformly fatal (Fig. 5.1). The avoidance of intubation using ventilatory strategies aimed at minimizing further lung injury may change the dismal prognosis associated with MV in HSCT recipients. Different studies have shown that early implementation of noninvasive ventilation (NIV) is indicated in an early stage of hypoxemic ARF in immunocompromised patients, since it decreases both the requirement of intubation and the incidence of nosocomial pneumonia, and consequently this ventilatory support might improve survival [43–45]. However, caution should be used concerning the unselective use of NIV in immunocompromised patients. Azulay et  al. [34] conducted a prospective study to identify factors associated with death in critically ill cancer patients admitted for ARF. These authors observed that mortality in patients treated with NIV who subsequently did not require conventional MV was only 15%, confirming the critical goal that this technique can add to the management of critically ill cancer patients. However, mortality in patients that required conventional MV after 72 h of NIV was very high. The absence of ­benefit from NIV in patients with severe lung involvement is in agreement with previous reports, suggesting that in selected cases NIV might have a deleterious impact by delaying conventional MV in patients who have ARDS and are managed

with ­nonoptimal ­diagnostic and treatment strategies. Depuydt et al. [46], in a retrospective revision of 26 patients with hematologic malignancies treated with NIV for ARF, could not demonstrate a survival benefit for the use of NIV in comparison with control patients receiving MV and matched for SAPS II. In this study, NIV was mainly used for the treatment of patients with acute severe hypoxic failure, and 60% of them required immediate endotracheal intubation as well as vasopressor therapy because of circulatory shock [45]. They hypothesized that the protective effect of NIV might be exerted only if applied immediately in an early, more compensated phase of their critical illness. In summary, based on the extremely poor prognosis of patients requiring MV and the promising results obtained with NIV, it seems logical to recommend the application of this type of ventilatory support to HSCT recipients with pulmonary infiltrates once significant respiratory failure has ensued. Further studies are needed to confirm these results and to determine the optimal duration of NIV in hematological patients.

5.4.4 Importance of Establishing a Specific Diagnosis HSCT recipients with pulmonary infiltrates need to be managed aggressively, and the underlying etiology must be identified as early as possible. The possibility

50

Frequency of organ failure (%)

45

Fig. 5.1  Differences in the incidence of organ failure between survivors (white segments) and nonsurvivors (black segments) (From [10])

40 35 30 25 20 15 10 5 0 Respirarory*

Cardiovascular*

Renal*

Hepatic*

Neurological*

5  Epidemiology of Acute Respiratory Failure in Patients with HM (ICU Only)

of non-infectious complications and the difficulty of making an antibiotic selection in light of growing resistance and the wide spectrum of potential etiologic factors emphasize the importance of designing strategies aimed at obtaining an early diagnosis. This is particularly true if we consider that inadequacy of the empirical treatment in the ICU setting increases the risk of death significantly [47]. In this sense, it has been shown that early diagnosis of both viral and fungal infections decreases mortality [48]. The use of both non-invasive and bronchoscopic techniques may facilitate the diagnosis in the majority of cases [49]. Some authors advocate the use of non-invasive diagnostic techniques as the cornerstone of the diagnostic workup of these patients, leaving bronchoscopic techniques for those selected patients with no evident risk of deterioration [50]. However, various studies in non-hypoxemic patients outside the ICU have shown that fiberoptic bronchoscopy is a low-risk procedure that can be performed in most patients and may add to the prompt identification of the specific etiologic agent, facilitating an etiology-guided treatment and avoiding unnecessary and potentially harmful additional treatment [51]. More controversial is whether or not the achievement of an early and specific diagnosis improves survival in HSCT recipients admitted to the ICU. Some investigators have reported that obtaining a specific diagnosis does not alter mortality in these patients [52–54]. Other researchers have reached different conclusions [51, 52]. The impact of diagnostic delay on mortality is an important emerging general theme in the care of seriously ill patients, particularly as it affects the adequacy of initial therapy [55]. Recommendations should focus on which is the best diagnostic strategy. In this sense, noninvasive techniques are increasingly used with success in these patients [52]. Bronchoscopy has, no doubt, an important role in the diagnosis, but a diligent analysis of its risk must be performed in each particular patient [52].

5.4.5 Other Factors Influencing Survival Interestingly, in patients who are selected for ICU admission, the characteristics of the underlying malignancy are not associated with survival. Thus, the response to chemotherapy, stage of the malignancy,

53

and other characteristics of the cancer have little or no impact on short-term survival [9]. The importance of leucopenia as a risk factor for mortality in critically ill patients with a hematologic malignancy is controversial. Different studies have reported a higher mortality in patients with prolonged neutropenia; however, this has not been confirmed by other authors [33]. The infectious etiology of the pulmonary complication has been classically considered as the most important cause of mortality in patients with a hematologic malignancy admitted to the ICU [7, 56], however, a recent study by Benoit et al. [8] reported a better prognosis in patients with documented bacterial infection than in those with non-bacterial pulmonary infections. Even in the absence of an identifiable bacterial microorganism, severely ill hematological patients admitted to the ICU with a clinical suspicion of bacterial infection had a better prognosis. Other factors that have been considered as early predictors of poor outcome are the use of vasopressors, high urea levels [33], the number and severity of organ failures [9], liver failure, use of glucocorticoids for treating GVHD, and interval time between transplantation and ICU admission. Although various retrospective analyses in immunocompromised patients indicate that higher APACHE II scores predict mortality [7], extrapolating a specific mortality rate to a particular patient is fraught with difficulty [55]. The information provided by general severity scores should only be considered in light of other clinical and more relevant variables. Finally, some specific complications have been identified as predictors of favorable outcome, such as the engraftment syndrome, congestive heart failure, and diffuse pulmonary hemorrhage [57].

5.5 Conclusions Over the last years, important advances in the management of hematological patients requiring ICU admission have taken place. As a result, survival in these patients has improved over the last decade. Thus, the general reluctance to admit patients with a hematologic malignancy to the ICU, even those with severe critical illness, is currently no longer justified. Not all transplanted patients with ARF can be expected to succumb. In the select, low-risk population of patients with autologous SCT with ARF, survival rates fall

54

within a range that we see for many other diseases that are routinely managed in ICU, such as sepsis-related ARDS [42]. In these patients, dedicated and aggressive support in the early phases of respiratory failure to attempt to establish an etiology seems warranted, allowing the early introduction of specific treatment. Early diagnosis is advantageous, and bronchoscopy, when carefully indicated, substantially increases the diagnostic yield, causing changes in the empirical treatment in the majority of patients [7]. The appropriate timing for withholding or withdrawal of support is probably the most contentious issue surrounding the care of these patients [42]. In patients in whom potential benefits of ICU admission are in doubt, a trial of full intensive ICU management should be given for a limited time period, during which daily evaluation of organ dysfunction may provide a more accurate prediction of survival than at admission [9].

References   1. Kotloff RM, Ahya VN, Crawford SW (2004) Pulmonary complications of solid organ and hematopoietic stem cell transplantation. Am J Respir Crit Care Med 170:22–48   2. Soubani AO, Kseibi E, Bander JJ et al (2004) Outcome and prognostic factors of hematopoietic stem cell transplantation recipients admitted to a medical ICU. Chest 126:1604–1611   3. Pène F, Aubron C, Azoulay E et al (2006) Outcome of critically ill allogeneic hematopoietic stem cell transplantation recipients: a reappraisal of indications for organ failure supports. J Clin Oncol 24:643–649   4. Khassawneh BY, White P Jr, Anaissie EJ et  al (2002) Outcome from mechanical ventilation after autologous peripheral blood stem cell transplantation. Chest 121: 185–188   5. Ewig S, Torres A, Riquelme R et al (1998) Pulmonary complications in patients with haematological malignancies treated at a respiratory ICU. Eur Respir J 12:116–122   6. Darmon M, Azoulay E, Alberti C et al (2002) Impact of neutropenia duration on short-term mortality in neutropenic critically ill cancer patients. Intensive Care Med 28: 1775–1780   7. Rañó A, Agustí C, Benito N et al (2002) Prognostic factors of non-HIV immunocompromised patients with pulmonary infiltrates. Chest 122:253–261   8. Benoit DD, Depydt PO, Peleman RA et  al (2005) Documented and clinically suspected bacterial infection precipitating intensive care unit admission in patients with hematological malignancies: impact on outcome. Int Care Med 31:934–942   9. Darmon M, Azoulay E (2009) Critical care management of cancer patients: cause for optimism and need for objectivity. Curr Opin Oncol 21:318–326

C. Agustí et al. 10. Lossos IS, Breuer R, Or R et al (1995) Bacterial pneumonia in recipients of bone marrow transplantation. A five-year prospective study. Transplantation 60(7):672–678 11. Dunagan DP, Am B, Hurd DD, Haponik EF (1997) Bronchoscopic evaluation of pulmonary infiltrates following bone marrow transplantation. Chest 111:135–141 12. Wingard JR (1999) Opportunistic infections after blood and marrow transplantation. Transpl Infect Dis 1(1):3–20 13. BitMansour A, Burns SM, Traver D (2002) Myeloid progenitors protect against invasive aspergillosis and Pseudomonas aeruginosa infection following hematopoietic stem cell transplantation. Blood 100:4660–4667 14. Haley CE, Cohen ML, Halter J et  al (1979) Nosocomial Legionnaire´s disease: a continuing common source epidemic at Wadsworth Medical Center. Ann Intern Med 90: 583–586 15. Marr KA, Carter RA, Boeckh M, Martin P, Corey L (2002) Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood 100(13):4358–66 16. Neofytos D, Horn D, Annaisie E et al (2009) Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry. Clin Infect Dis 48:265–273 17. Wingard J, Merz W, Rinaldi M et al (1991) Increase in candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole. N Engl J Med 325:1274–1277 18. Horn DL, Neofytos D, Anaissie EJ et al (2009) Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry. Clin Infect Dis 48:1695–1703 19. Lyratzopoulos G, Ellis M, Nerringer R et al (2002) Invasive infection due to penicillium species other than P. marneffei. J Infect 45:184–195 20. Marr KA, Carter RA, Crippa F et al (2002) Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 34:909–917 21. De Hoog GS, Marvin-Sikkema FD, Lahpoor GA et al (1994) Ecology and physiology of the emerging opportunistic fungi Pseudallescheria boydii and Scedosporium prolificans. Mycoses 37:71 22. Kovacs JA, Masur H (2009) Evolving health effects of Pneumocystis: one hundred years of progress in diagnosis and treatment. JAMA 301:2578–2585 23. De Castro N, Neuville S, Sarfati C et al (2005) Occurrence of Pneumocystis jiroveci pneumonia after allogeneic stem cell transplantation: a 6-year retrospective study. Bone Marrow Transplant 36(10):879–883 24. Sullivan KM, Dykewicz CA, Longworth DL et  al (2001) Preventing opportunistic infections after hematopoietic stem cell transplantation: the Centers for Disease Control and Prevention, Infectious Diseases Society of America, and American Society for Blood and Marrow Transplantation Practice Guidelines and beyond. Hematology Am Soc Hematol Educ Program 2001:392–421 25. Taplitz RA, Jordan MC (2002) Pneumonia caused by herpes viruses in recipients of hematopoietic cell transplants. Semin Respir Infect 17:121–129 26. Boeckh M, Leisenring W, Riddell SR et al (2003) Late cytomegalovirus disease and mortality in recipients of allogeneic

5  Epidemiology of Acute Respiratory Failure in Patients with HM (ICU Only) hematopoietic stem cell transplants: importance of viral load and T-cell immunity. Blood 101:407–414 27. Chemaly RF, Ghosh S, Bodey GP et al (2006) Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center. Medicine (Baltimore) 85: 278–287 28. Bowden RA (1997) Respiratory virus infections after marrow transplant: the Fred Hutchinson Cancer Research Center experience. Am J Med 102:27–30, discussion 42-3 29. Fischer SA (2008) Emerging viruses in transplantation: there is more to infection after transplant than CMV and EBV. Transplantation 86:1327–1339 30. Buchbinder S, Elmaagacli AH, Schaefer UW, Roggendorf M (2000) Human herpesvirus 6 is an important pathogen in infectious lung disease after allogeneic bone marrow transplantation. Bone Marrow Transplant 26:639–44 31. Schuster DP, Marion JM (1983) Precedents for meaningful recovery during treatment in a medical intensive care unit. Am J Med 75:402–408 32. Benoit DD, Vandewoude KH, Decruyenaere JM, Hoste EA, Colardyn FA (2003) Outcome and early prognostic indicators in patients with a hematologic malignancy admitted to the intensive care unit for a life-threatening complication. Crit Care Med 31:104–112 33. Dane N, Maziarz RT, Haupt MT (1999) Mechanical ventilation in hematopoietic stem cell transplant patients: is there need for re-evaluation? Chest 116:857–859 34. Azoulay E, Thièry G, Chevret S et al (2004) The prognosis of acute respiratory failure in critically ill cancer patients. Medicine 83:360–370 35. Van Gestel J, Bollen C, Van der Tweel I et al (2008) Intensive care unit mortality trends in children after hematopoietic stem cell transplantation: a meta-regression analysis. Crit Care Med 36:2898–2904 36. Thiery G, Azoulay E, Darmon M et al (2005) Outcome of cancer patients considered for intensive care unit admission: a hospital-wide prospective study. J Clin Oncol 23: 4406–4413 37. Parker RI (2008) Paediatric intensive care unit outcome following paediatric hematopoietic stem cell transplantation: Quo Vadis? Crit Care Med 36:2954–2955 38. Shorr AF, Moores LK, Edenfield WJ et  al (1999) Mechanical ventilation in hematopoietic stem cell transplantation. Can we effectively predict outcomes? Chest 116:1012–1018 39. Bach PB, Schrag D, Nierman DM et al (2001) Identification of poor prognostic features among patients requiring mechanical ventilation after hematopoietic stem cell transplantation. Blood 93:3234–3240 40. Price KJ, Thall PF, Kish SK et al (1998) Prognostic indicators for blood and marrow transplant patients admitted to an intensive care unit. Am J Respir Crit Care Med 158: 876–884 41. Nichols DJ, Maziarz RT, Haupt MT (1999) Mechanical ventilation in hematopoietic stem cell transplant recipients: is there need for reevaluation? Chest 116:857–859

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42. Esteban A, Anzueto A, Frutos F et al (2002) Characteristics and outcomes in adult patients receiving mechanical ventilation. A 28-day international study. JAMA 287:345–355 43. Antonelli M, Conti C, Rocco M et al (1998) A comparison of noninvasive positive-pressure ventilation and conventional mechanical ventilation in patients with acute respiratory failure. N Engl J Med 339:429–435 44. Hilbert G, Gruson D, Vargas F et  al (2001) Noninvasive ­ventilation in immunocompromised patients with pulmonary infiltrates, fever, and acute respiratory failure. N Engl J Med 95:358–364 45. Azoulay E, Alberti C, Bornstain C et  al (2001) Improved survival in cancer patients requiring mechanical ventilatory support: impact of noninvasive mechanical ventilatory support. Crit Care Med 29:519–525 46. Depuydt PO, Benoit DD, Vandewoude KH et  al (2004) Outcome in noninvasively and invasively ventilated hematologic patients with acute respiratory failure. Chest 126: 1299–1306 47. Ibrahim EH, Sherman G, Ward S et al (2000) The influence of inadequate antimicrobial treatment of blood stream infections on patient outcomes in the ICU setting. Chest 118: 146–155 48. Elizaga J, Olavarria E, Apperley JF et al (2001) Parainfluenzae virus 3 infection after stem cell transplant: relevance to outcome of rapid diagnosis and ribavirin treatment. Clin Infect Dis 32:413–418 49. Rañó A, Agustí C, Jiménez P et al (2001) Pulmonary infiltrates in non-HIV immunocompromised patients: a diagnostic approach using non-invasive and bronchoscopic procedures. Thorax 56:379–387 50. Azoulay E, Mokart D, Rabbat A et  al (2008) Diagnostic bronchoscopy in hematology and oncology patients with acute respiratory failure: prospective multicenter data. Crit Care Med 36:100–107 51. Shorr AF, Susla GM, O’Grady NP (2004) Pulmonary infiltrates in the non-HIV-infected immunocompromised patient: etiologies, diagnostic strategies and outcomes. Chest 125: 260–271 52. White D, Bonacum JT, Miller CB (1997) Utility of fiberoptic bonchoscopy in bone marrow transplant patients. Bone Marrow Transplant 20:681–687 53. Murray PV, O´Brien ME, Padhani AR et  al (2001) Use of first line bronchoalveolar lavage in the immunosuppressed oncology patient. Bone Marrow Transplant 27:967–71 54. Poe RH, Wahl GW, Qazi R et al (1986) Predictors of mortality in immunocompromised patients with pulmonary infiltrates. Arch Intern Med 146:1304–1308 55. Shorr AF, Kollef MH (2002) The quick and the dead: the importance of rapid evaluation of infiltrates in the immunocompromised patient. Chest 122:9–12 56. Groeger JS, White P, Nierman DM et al (1999) Outcome for cancer patients requiring mechanical ventilation. J Clin Oncol 17:991–997 57. Lee CK, Gingrich RD, Hohl RJ et al (1995) Engraftment syndrome in autologous bone marrow and peripheral stem cell transplantation. Bone Marrow Transplant 16:175–182

 

6

Noninfectious Lung Involvement in Patients with Hematological Malignancies (Excluding BMT) Bernard Maitre

Contents

6.1 Epidemiology

6.1 Epidemiology........................................................... 57 6.2 Venous Thromboembolism in the Hematologic Malignancies..................................... 6.2.1 Lymphoma................................................................ 6.2.2 Acute Leukemia........................................................ 6.2.3 Multiple Myeloma....................................................

57 58 58 58

6.3 Drug-Induced Lung Toxicity................................. 58 6.4 Lung Diseases Induced by Radiation of the Chest.............................................................. 59 6.5 Secondary Lung Cancers....................................... 60 6.5.1 Hodgkin’s Lymphoma.............................................. 60 6.5.2 Second Cancers Following Bone Marrow Transplantation............................................ 60 6.6 Other Lung Diseases............................................... 6.6.1 Pulmonary Extramedullary Hematopoiesis.............. 6.6.2 Pulmonary Hypertension and Myelofibrosis............ 6.6.3 Alveolar Proteinosis..................................................

61 61 61 61

6.7 Summary................................................................. 61 References............................................................................ 62

B. Maitre  Service de Pneumologie, Hôpitaux Henri Mondor et intercommunal, Créteil, Université Paris XII, PRES EST France e-mail: [email protected]

Patients with hematological malignancies frequently experience pulmonary diseases, and these complications represent a difficult challenge for physicians. The aim of this chapter is not to give an exhaustive review of noninfectious causes of lung involvement in these patients, but to highlight the frequency of some of well-known lung diseases. We have made the choice to examine three different aspects of noninfectious lung involvement in hematological patients that are also covered in three different chapters in this book, namely, thromboembolism, secondary cancers and treatmentrelated pulmonary toxicity. Our major goal is to ­illu­strate the wide spectrum of lung diseases in hematological patients.

6.2 Venous Thromboembolism in the Hematologic Malignancies Patients with hematological malignancies are well known to be at high risk of hemorrhagic complications, but are also at high risk of venous thromboembolism (VTE) [11]. Dr. Khorana has contributed a specific chapter on this topic in this book. Compared with the estimated annual incidence of VTE in the general population, the incidence of 0.1–0.5% in the cancer population appears in the ranges of VTE in patients with high-risk solid tumors [18]. Immobility, age, previous thrombotic history, venous stasis and infection are all disease-host risk factors for VTE. Treatment-related risk factors, such as chemotherapy, hormone therapy, erythropoiesis-stimulating factor or central venous devices, can participate to the general risk [15].

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_6, © Springer-Verlag Berlin Heidelberg 2011

57

58

Current published data allow estimation of VTE rates in patients with lymphoma, acute leukemia (AL) and multiple myeloma (MM).

6.2.1 Lymphoma In a large cohort study from Khorana et al., lymphoma was associated with the third risk level of thrombosis after upper gastrointestinal cancers and lung cancers [15]. The retrospective analysis from [24] found a global VTE incidence of 7.7%, with a significantly higher rate in patients with high-grade lymphoma (10.6%). The thrombosis incidence is even higher in CNS lymphoma patients mostly receiving methotrexate (59.5%) [12]. Two studies have prospectively evaluated the incidence of VTE in lymphoma. The VTE rate was estimated between 6.6% and 8.6% depending on the type of lymphoma (Hodgkin’s disease versus non-Hodgkin’s lymphoma) and chemotherapy regimens [15, 26]. A platelet count higher than 350,000 mm3 and vessel compression by the tumor were risk factors for VTE.

6.2.2 Acute Leukemia Thrombotic events have been described to be less ­frequent than hemorrhages in AL patients, particularly in acute promyelocytic leukemia. However, recent studies suggest a significant rate of thrombosis, which can vary from 1.4% to 12% depending on the timing: at diagnosis or during remission induction therapy. A large population-based cohort study of patients with AL, AML or ALL was used to determine the incidence and risk factors associated with development of VTE. The 2-year cumulative incidence of VTE was 5.2% in AML and 4.5% in ALL [17]. In AML patients, female sex, older age, number of chronic comorbidities, and presence of a catheter were significant predictors of development of VTE within 1 year. A diagnosis of VTE was not associated with reduced survival in AML patients. Risk factors for VTE in ALL patients were presence of a central venous catheter, older age and number of chronic comorbidities. In the patients with ALL, development of VTE was associated with a 40% increase in the risk of dying within 1 year. In acute lymphoid leukemia, two meta-analyses found an incidence of 5.2% (children) to 5.9% (adults) of thrombotic events [5, 6].

B. Maitre

6.2.3 Multiple Myeloma Ten percent of patients with MM will develop a VTE. Thalidomide and its derivative increase the response of treatment, but when these drugs are associated with doxorubicin or dexamethasone, the risk of VTE is two or three times more likely [3, 10]. Few data are available for lenalidomide, but it seems associated with an increase of thrombotic events, particularly in combination with dexamethasone (6% vs. 2%) [22]. A recent study combining results and follow-up of two randomized protocols, including 353 patients with MM, showed a thromboembolic event in 17% of patients. However, contrary to patients with solid cancer, it is not associated with shorter survival [32].

6.3 Drug-Induced Lung Toxicity Infiltrative lung diseases related to the use of antineoplastic agents are being increasingly described in patients with hematological malignancies. A chapter from Camus and coworkers covers this topic very well in this book. Although the pulmonary toxicity of old agents is well known, they contribute little to significant pulmonary disease. However, newer drugs or old drugs with new indications (such as thalidomide in MM) increase the incidence of such complications substantially. Regarding epidemiological data, conversely to VTE, no specific diagnostic criteria are set up to report on precise the incidence of drug-induced lung diseases. Drugs can produce all histological patterns of interstitial pneumonia, and there are no specific histological criteria for drug-induced lung disease. The diagnosis rests on a temporal association between exposure and the development of respiratory symptoms. Since patients with hematological malignancies are often being treated at the same time by different antineoplastic drugs or exposed to a wide variety of others medications, with potential lung toxicity, increased difficulties exist when trying to affirm the relation between one drug and lung toxicity. The incidence of drug-induced lung toxicities varies considerably from 0.1% to 15% of patients with hematological malignancies. It has to be noted that concomitant use of steroids does not necessarily prevent the development of lung toxicities (Table 6.1).

6  Noninfectious Lung Involvement in Patients with Hematological Malignancies (Excluding BMT)

59

Table 6.1  Antineoplastic agents associated with lung disease Agent

Class

Incidence

Frequency

Anthracyclines

Cytotoxic antibiotics

<0.1

Azacytidine

Demethylating agent

<5

Bleomycin

Antineoplastic antibiotic

Bortezomib

Proteasome inhibitor

Busulfan

Alkylating agent

c

Carmustine

Nitrosourea

c

Cladribine

Purine analog

Cyclophosphamide

Alkylating agent

c

Cytosine Arabinoside

Antimetabolite analog

b

Dasatinib

Tyrosine kinase inhibitor

Etoposide

Topoisomerase inhibitor

Fludarabine

Purine analog

Gemcitabine

Antimetabolite

b

Hydroxyurea

Antimetabolite

b

Imatinib

Tyrosine kinase inhibitor

<1.3

a

Interferon-alpha

Interferon

1.5

b

Lenalidomine

Thalidomide derivative

6

a

Lomustine

Nitrosourea

b

Melphalan

Alkylating agent

b

Methotrexate

Antimetabolite agent

c

Procarbazine

Alkylating agent

<0.1

b

Rituximab

Monoclonal antibody

<0.1

b

Thalidomide

Thalidomide

<0.1

a

Trofosfamide

Alkykating agent

<0.1

a

Vinblastine

Vinca alkaloid

a c

15

<0.1

<0.1

a

a

b c

<9

b

c

Pneumotox® website [4] a Isolated cases b 10 cases reported c 20–100 cases reported Adapted from http://pneumotox.com

6.4 Lung Diseases Induced by Radiation of the Chest Radiation lung toxicity can develop during or following radiation therapy for Hodgkin’s or non-Hodgkin’s lymphoma, or total body irradiation (TBI). Gallego and Rello have covered this topic very nicely in this book. Variation in study population, treatment regimen

and criteria for radiation pneumonia diagnosis hampers the comparison of patient cohorts across different studies. In contrast to allogeneic BMT studies, the incidence of pneumonitis is low (between 0% and 16%). In a study of 94 patients who underwent BMT using an escalated TBI-containing conditioning regimen, Chen and coworkers looked at pretransplant variables that predict radiation-induced pneumonitis [7]. They failed to find predictable variables other than

60

pretransplant hemoglobin less than 100 g/L. This suggests that TBI itself is the main factor, and this has been confirmed by comparison with others cohorts of patients with lymphoma who have been treated by the same conditioning regimen with or without TBI [7]. This has been confirmed in patients with MM. Unacceptable risk of pulmonary fibrosis has been described in regimens combining radiation and drugs, such as gemcitabin, vinblastin, bleomycin and methotrexate. However, in one study of 60 early stage Hodgkin’s lymphoma (HL) patients receiving an ABVD regimen, adding mediastinal radiotherapy was associated with a significant decrease in FVC and DLCO. This worsening respiratory function was observed in 37% of patients, but with no translation into clinical symptoms [14]. Mediastinal emphysema and pneumothorax have also been described in case series, and a frequency of 2.2% has been proposed for Hodgkin’s patient without previous lung disease and treated by mantle radiation therapy [27, 28]. This suggests a pathophysiologic link between apical fibrosis and onset of pneumothorax. Strikingly, most patients were asymptomatic. Radiation can also cause vasculopathy with intimal damage in both arterioles and veinules. Different case reports have emphasized the risk of veno-occlusive disease of the liver but also the lung following TBI and a conditioned regimen before bone marrow transplantation, but case reports described this complication in patients following radiation in a mantle distribution [16, 19].

6.5 Secondary Lung Cancers Although the possibility of a malignant involvement in different organs is possible and frequent in hematological malignancies, secondary malignancy as a result of long-term complications of treatment is one of the most concerning problems for physicians.

6.5.1 Hodgkin’s Lymphoma Solid tumors account for more than one-half of second malignancies developing after 15 or more years of follow-up in patients treated for HL. Although no

B. Maitre

prospective study has reported the occurrence of a new second cancer, 20 retrospective studies with long-term outcomes have been published [20]. In this study, relative risk and absolute excess risk of second malignant disease in 32,591 patients treated for HL were as ­follows: for all solid tumors, RR 2.0 (1.9–2.4) and absolute excess risks of 33.1; for esophagus, 2.8 (1.8–4.0) and 0.7, for stomach, 1.5 (0.3–3.5) and 0.1; for small intestine 1.9 (1.5–2.4) and 1.5; for colon, 2.9 (2.6–3.2) and 9.7; for the lung 1.6 (1.4–1.9) and 2.0; for female breast, 9.9 (8.7– 11.2) and 8.8 [20]. Lung cancer frequencies varied across studies: 1/3 of solid tumors in the British National Lymphoma Organization and less than 10% in the American study [29, 30]. Risk of lung cancer is significantly increased in patients who have been treated for HL[21, 25]. The median relative risk of a second lung cancer ranges from 2.6 to 7. Several risk factors have been described: (1) age at treatment older than 45 years; (2) time since treatment, but above 20–30 years after treatment the risk falls to that of the untreated population; (3) the treatment modality is an important risk factor: an increased number of cycles >9 or a MOPP regimen; radiotherapy is a more important factor than chemotherapy itself, increasing the radiation dose up to 40 Gy; (4) the smoking habit, smoking at the time of treatment or current smokers can increase the risk for lung cancer [30], but not the amount smoked before diagnosis [31]. There appears to be a more than multiplicative relation between smoking-related and radiationrelated or alkylating agent risk (Table 6.2). Contrarily, gender, splenic involvement or splenectomy and combined modality do not appear to be associated with a high risk.

6.5.2 Second Cancers Following Bone Marrow Transplantation In the largest study conducted to date among 19,229 recipients of allogeneic and syngeneic HCT, the cumulative incidence of second cancers at 5, 10 and 15 years after transplantation was 0.7%, 2.2% and 6.7%, respectively. In the general population, these rates are of 0.3%, 0.6% and 0.8% [23].

6  Noninfectious Lung Involvement in Patients with Hematological Malignancies (Excluding BMT)

61

Table 6.2  Risk of developing lung cancer in Hodgkin’s lymphoma patients depending on treatment regimens and smoking habits Relative risk [95% CI] Radiation > 5 Gy Alkylating agents Smoking habits in the 5 years before diagnosis of lung cancer −

−

–

1.0a

−

+

−

4.3 [2–12]

−

−

+

6.0 [2–20]

+

−

−

7.2 [3–21]

+

+

−

7.2 [3–22]

–

+

+

16.8 [6–53]

+

−

+

20.2 [7–68]

+

+

+

49.1 [15–187]

Data from Travis et al. [30] a The reference group consisted of 21 patients with lung cancer and 98 control patients who received a radiation dose of less than 5 Gy to the specific location in the lung where the cancer was diagnosed

6.6 Other Lung Diseases

6.6.3 Alveolar Proteinosis

6.6.1 Pulmonary Extramedullary Hematopoiesis

In a retrospective study, Fleury Feith and colleagues estimated the incidence of this rare complication at 5.3% among all the hematologic population and 10% in patients with myeloid disorders [8]. The study is based on a BAL retrospective study, but may represent in most cases a more surfactant dysfunction than a lung disease. Alveolar proteinosis is covered by the contribution to this book by Vincent and Tandjaoui.

Acute respiratory failure and pulmonary fibrosis have been described in patients with agnogenic myeloid metaplasia, but parenchymal nodules and pleural effusion have been described as well [1, 2].

6.6.2 Pulmonary Hypertension and Myelofibrosis An association between pulmonary hypertension and myeloproliferative diseases has been suggested in small series [9]. For these reasons, it is difficult to estimate the incidence of this complication, but it is probably a rare disease. It has been suggested that there are two distinct forms of pulmonary hypertension [13]. Chronic thromboembolism disease is a common complication of myeloproliferative disease and can induce pulmonary hypertension. This form of pulmonary hypertension occurred more frequently in the first 2  years. Arterial pulmonary hypertension seems less frequent and occurred in a late course of the disease, suggesting that myeloid infiltration participates in the physiopathology.

6.7 Summary Noninfectious lung involvement in patients with hematological malignancies is a frequent condition. If infectious disease and cardiogenic pulmonary edema are the most frequent complications, VTE and druginduced lung toxicity could potentially be detected early during the hematological disease. Risk of lung cancers is significantly increased in patients with CLL, those treated for lymphoma or those who underwent bone marrow transplantation. This emphasized the need to encourage patients to stop smoking, and a screening program for lung cancer in high-risk patients (age >45 years, chest irradiation and smokers) should be discussed.

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References   1. Asakura S, Colby TV (1994) Agnogenic myeloid metaplasia with extramedullary hematopoiesis and fibrosis in the lung. Report of two cases. Chest 105:1866–1868   2. Bartlett RP, Greipp PR, Tefferi A et al (1995) Extramedullary hematopoiesis manifesting as a symptomatic pleural effusion. Mayo Clin Proc 70:1161–1164   3. Baz R, Li L, Kottke-Marchant K et  al (2005) The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma. Mayo Clin Proc 80:1568–1574   4. Camus P, Foucher P Pneumotox® website (1997) Last update 2009 http//pneumotox.com.   5. Caruso V, Iacoviello L, Di Castelnuovo A et al (2007) Venous thrombotic complications in adults undergoing induction treatment for acute lymphoblastic leukemia: results from a meta-analysis. J Thromb Haemost 5:621–623   6. Caruso V, Iacoviello L, Castelnuovo D et  al (2006) Thrombotic complications in childhood acute lymphob­lastic leukemia: a meta-analysis of 17 prospective studies comprising 1, 752 pediatric patients. Blood 108:2216–2222   7. Chen CI, Abraham R, Tsang et  al (2001) Radiationassociated pneumonitis following autologous stem cell transplantation: predictive factors, disease characteristics and treatment outcomes. Bone Marrow Transplant 27: 177–182   8. Cordonnier C, Fleury-Feith J, Escudier E et  al (1994) Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients. Am J Respir Crit Care Med 149:788–794   9. Dingli D, Utz JP, Krowka MJ et al (2001) Unexplained pulmonary hypertension in chronic myeloproliferative disorders. Chest 120:801–808 10. El Accaoui RN, Shamseddeen WA, Taher AT (2007) Thalidomide and thrombosis. A meta-analysis. Thromb Haemost 97:1031–1036 11. Falanga A, Marchetti M (2009) Venous thromboembolism in the hematologic malignancies. J Clin Oncol 27: 4848–4857 12. Goldschmidt N, Linetsky E, Shalom E, Varon D, Siegal T (2003) High incidence of thromboembolism in patients with central nervous system lymphoma. Cancer 98: 1239–1242 13. Guilpain P, Montani D, Damaj G et  al (2008) Pulmonary hypertension associated with myeloproliferative disorders: a retrospective study of ten cases. Respiration 76:295–302 14. Hirsch A, Vander Els N, Straus DJ et al (1996) Effect of ABVD chemotherapy with and without mantle or mediastinal irradiation on pulmonary function and symptoms in early-stage Hodgkin’s disease. J Clin Oncol 14: 1297–1305 15. Khorana AA, Francis CW, Culakova E et  al (2005) Risk ­factors for chemotherapy-associated venous thromboembolism in a prospective observational study. Cancer 104: 2822–2829

B. Maitre 16. Kramer MR, Estenne M, Berkman N et al (1993) Radiationinduced pulmonary veno-occlusive disease. Chest 104: 1282–1284 17. Ku GH, White RH, Chew HK et al (2009) Venous thromboembolism in patients with acute leukemia: incidence, risk factors, and effect on survival. Blood 113:3911–3917 18. Lee AY, Levine MN (2003) Venous thromboembolism and cancer: risks and outcomes. Circulation 107:I17–21 19. Lombard CM, Churg A, Winokur S (1987) Pulmonary venoocclusive disease following therapy for malignant neoplasms. Chest 92:871–876 20. Lorigan P, Radford J, Howell A et  al (2005) Lung cancer after treatment for Hodgkin’s lymphoma: a systematic review. Lancet Oncol 6:773–779 21. Mauch PM, Kalish LA, Marcus KC et  al (1996) Second malignancies after treatment for laparotomy staged IA-IIIB Hodgkin’s disease: long-term analysis of risk factors and outcome. Blood 87:3625–3632 22. Menon SP, Rajkumar SV, Lacy M et  al (2008) Thromboembolic events with lenalidomide-based therapy for multiple myeloma. Cancer 112:1522–1528 23. Metayer C, Curtis RE, Vose J et al (2003) Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: a multicenter case-control study. Blood 101:2015–2023 24. Mohren M, Markmann I, Jentsch-Ullrich et  al (2006) Increased risk of venous thromboembolism in patients with acute leukaemia. Br J Cancer 94:200–202 25. Ng AK, Bernardo P, Weller E et al (2002) Second malignancy after Hodgkin disease treated with radiation therapy with or without chemotherapy: long-term risks and risk factors. Blood 100:1989–1996 26. Ottinger H, Belka C, Kozol et al (1995) Deep venous thrombosis and pulmonary artery embolism in high-grade non Hodgkin’s lymphoma: incidence, causes and prognostic relevance. Eur J Haematol 54:186–194 27. Pezner RD, Horak DA, Sayegh HO et al (1990) Spontaneous pneumothorax in patients irradiated for Hodgkin’s disease and other malignant lymphomas. Int J Radiat Oncol Biol Phys 18:193–198 28. Shapiro SJ, Shapiro SD, Mill WB et al (1990) Prospective study of long-term pulmonary manifestations of mantle irradiation. Int J Radiat Oncol Biol Phys 19:707–714 29. Swerdlow AJ, Douglas AJ, Hudson GV et al (1992) Risk of second primary cancers after Hodgkin’s disease by type of treatment: analysis of 2846 patients in the British National Lymphoma Investigation. BMJ 304:1137–1143 30. Travis LB, Gospodarowicz M, Curtis RE et al (2002) Lung cancer following chemotherapy and radiotherapy for Hodgkin’s disease. J Natl Cancer Inst 94:182–192 31. van Leeuwen FE, Klokman WJ, Stovall M et al (1995) Roles of radiotherapy and smoking in lung cancer following Hodgkin’s disease. J Natl Cancer Inst 87:1530–1537 32. Zangari M, Tricot G, Polavaram L et  al (2010) Survival effect of venous thromboembolism in patients with multiple myeloma treated with lenalidomide and high-dose dexamethasone. J Clin Oncol 28:132–135

7

Noninfectious Pulmonary Involvement in Hematopoietic Stem Cell or Bone Marrow Transplant Recipients Bekele Afessa

Contents 7.1 Introduction............................................................. 63 7.2 Pulmonary Function Abnormalities..................... 64 7.3 Asthma..................................................................... 66 7.4 Acute Pulmonary Edema....................................... 66 7.5 Bronchiolitis Obliterans......................................... 7.5.1 Incidence and Risk Factors....................................... 7.5.2 Pathogenesis............................................................. 7.5.3 Clinical Findings and Diagnostic Evaluation........... 7.5.4 Treatment.................................................................. 7.5.5 Clinical Course......................................................... 7.6 Bronchiolitis Obliterans Organizing Pneumonia (BOOP)................................................ 7.6.1 Incidence and Pathogenesis...................................... 7.6.2 Clinical Presentation and Diagnostic Evaluation................................................................. 7.6.3 Treatment and Prognosis.......................................... 7.7 Idiopathic Pneumonia Syndrome (IPS)................ 7.7.1 Epidemiology............................................................ 7.7.2 Clinical Findings and Diagnostic Evaluation........... 7.7.3 Treatment.................................................................. 7.7.4 Clinical Course and Prognosis..................................

66 66 67 67 68 69

7.12 Pulmonary Veno-Occlusive Disease (PVOD)....... 7.12.1 Pathogenesis............................................................. 7.12.2 Clinical Findings and Diagnostic Evaluation........... 7.12.3 Treatment and Prognosis..........................................

74 74 74 75

7.13 Other Pulmonary Complications.......................... 7.13.1 Pulmonary Arterial Hypertension............................. 7.13.2 Pulmonary Alveolar Proteinosis............................... 7.13.3 Chronic Eosinophilic Pneumonia.............................

75 75 75 76

References............................................................................ 76

70 71

7.1 Introduction

71 71 71 71 72

Worldwide, tens of thousands of patients undergo blood and marrow transplants (BMT) each year, mainly for hematologic disorders [1]. BMT recipients are often treated with a conditioning regimen before the transplant. Conditioning regimens with total body irradiation ³500 cGY, single fractionated dose ³800 cGY, busulfan doses of >9 mg/kg, or malphalan doses of >150 mg/m2 given as single agents or in combination with other agents are considered myeloablative. Conditioning regimens with lower doses of total body irradiation, fractionated doses, busulfan, and malphalan than those used in myeloablative regimens are considered non-myeloablative or lower intensity conditioning regimens. The majority of BMT performed worldwide is autologous. Mobilized peripheral blood stem cells are the main graft source for autologous BMT, accounting for >90% [1]. Bone marrow is the primary graft source in children undergoing allogeneic BMT. However, the use of peripheral blood and umbilical blood grafts in children is increasing. During the period

72 72 72 72

7.10 Delayed Pulmonary Toxicity Syndrome (DPTS)..................................................................... 72 7.10.1 Clinical Findings and Diagnostic Evaluation........... 73 7.10.2 Treatment and Prognosis.......................................... 73

B. Afessa  Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905, USA e-mail: [email protected]

73 73 73 74

69 69

7.8 Diffuse Alveolar Hemorrhage (DAH)................... 72 7.9 Periengraftment Respiratory Distress Syndrome (PERDS).................................................................. 7.9.1 Epidemiology............................................................ 7.9.2 Clinical Findings and Diagnostic Evaluation........... 7.9.3 Treatment and Prognosis..........................................

7.11 Pulmonary Cytolytic Thrombi (PCT)................... 7.11.1 Pathogenesis............................................................. 7.11.2 Clinical Findings and Diagnostic Evaluation........... 7.11.3 Treatment and Prognosis..........................................

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_7, © Springer-Verlag Berlin Heidelberg 2011

63

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B. Afessa

from 2003 to 2007, peripheral blood and umbilical cord blood grafts accounted for 28% and 20%, respectively, of allogeneic BMT in children [1]. Peripheral blood is the source of allogeneic graft in approximately 80% of BMT recipients older than 20 years. The most common indications for BMT are multiple myeloma and lymphoma, accounting for 63% in North America [1]. Multiple myeloma is the most common indication for autologous transplantation and acute myelogeneic leukemia for allogeneic transplantation. The post-transplant period is divided into three phases: pre-engraftment (0–30 days), early postengraftment (30–100 days), and late post-transplant (>100 days). BMT recipients’ underlying diseases, the chemotherapy and radiation therapy they receive to treat the underlying diseases, and the conditioning regimen result in damage to multiple organ systems. Pulmonary complications develop in 30–60% of BMT recipients [2–4]. The pulmonary complications follow characteristic time patterns [5]. With the widespread use of prophylaxis for certain infections, the spectrum of pulmonary complications following BMT has shifted from more infectious to non-infectious complications [6]. Among the non-infectious pulmonary complications, pulmonary edema, diffuse alveolar hemorrhage (DAH), and peri-engraftment respiratory distress syndrome (PERDS) usually occur during the first 30 days following transplant (Fig.  7.1). Idiopathic pneumonia syndrome (IPS) can occur at any time following transplant. We will review the main non-infectious pulmonary complications in this chapter (Tables 7.1 and 7.2).

Table  7.1  Noninfectious pulmonary complications in blood and marrow transplant recipients Isolated abnormality in pulmonary function Asthma Acute pulmonary edema Bronchiolitis obliterans Bronchiolitis obliterans organizing pneumonia Idiopathic pneumonia syndrome Diffuse alveolar hemorrhage Peri-engraftment respiratory distress syndrome Delayed pulmonary toxicity syndrome Pulmonary cytolytic thrombi Pulmonary veno-occlusive disease Progressive pulmonary fibrosis Pulmonary hypertension Hepatopulmonary syndrome Pulmonary alveolar proteinosis Eosinophilic pneumonia

7.2 Pulmonary Function Abnormalities Pulmonary function test (PFT) in BMT recipients has shown that restrictive and obstructive ventilatory defects and gas transfer abnormalities are frequent

DAH APE PERDS BOOP PCT IPS BO Acute GVHD 0

1

2

Chronic GVHD 3

4

5

6

7

8

9

10

11

12

Months Phase I

Phase II

Fig. 7.1  Timing of the major non-infectious complications following blood and marrow transplantation. BO Bron­ chiolitis obliterans, DAH diffuse alveolar hemorrhage, GVHD graft-versus-host-disease, IPS idiopathic pneumonia

Phase III

syndrome, P edema pulmonary edema, PERDS peri-engraftment respiratory distress syndrome, Phase I pre-engraftment period, Phase II early post-engraftment period, phase III late post-engraftment period

7  Noninfectious Pulmonary Involvement in Hematopoietic Stem Cell or Bone Marrow Transplant Recipients Table 7.2  Characteristics of selected pulmonary complications in BMT recipients Characteristics BO BOOP DAH

PERDS

IPS

Incidence

3.8% in allogeneic, rare in autologous

Low

5%

5%

10%

Clinical features

Dyspnea

Dyspnea

Dyspnea

Dyspnea

Cough

Cough

Cough

Cough

Fever

Dyspnea

Wheezing

Fever

Fever

Airway obstruction

↓¯ TLC

↓¯ TLC

↓¯ DLCO

↓¯ DLCO

PFT

Radiographic features

Air trapping

Consolidation

Infiltrates

Hyperinflation

Ground-glass opacity

Ground-glass opacities

Normal

Infiltrates

Diffuse infiltrates

Clinical Bronchoscopy

Bronchoscopy

65

Nodular opacity Definite diagnosis

Surgical biopsy

Surgical biopsy

Bronchoscopy

Transbronchial biopsy

Surgical biopsy

Treatment

Immunosuppressant

Steroids

Steroids

Steroids

None

Case fatality

High (59%)

Low (19%)

High (80%)

26%

74%

BMT Hematopoietic peripheral blood and bone marrow stem cell transplant, BO bronchiolitis obliterans, BOOP bronchiolitis o­ bliterans organizing pneumonia, DAH diffuse alveolar hemorrhage, DLCO diffusion of carbon monooxide, IPS idiopathic pneumonia ­syndrome, PERDS peri-engraftment respiratory distress syndrome, PFT pulmonary function test, TLC total lung capacity

long-term sequelae, particularly following allogeneic transplantation [6, 7]. A systematic review of 20 publications published between 1996 and 2001 found decreased carbon monoxide diffusion (DLCO) in 83%, restriction in 35%, and obstruction in 23% of allogeneic BMT recipients [8]. A retrospective cohort study of over 500 BMT recipients from the University of Toronto covering a more contemporary period of 1980–1997 documented somewhat lower frequencies: impaired diffusion in 35%, restriction in 12%, and obstruction in only 6% of long-term survivors [9]. While the frequency of restriction and impaired diffusion appeared constant over time, this study suggested a declining frequency of airflow obstruction: 15% in patients transplanted before 1987 compared to 5% for those receiving transplantation after 1987. The extremely low incidence of airflow obstruction documented in this study likely reflects the very stringent diagnostic criteria utilized by the authors. Utilizing a more sensitive definition, Chien and colleagues identified airflow obstruction in 26% of long-term survivors

of allogeneic BMT in a contemporary series from the Fred Hutchinson Cancer Center [10]. Notably, the development of airflow obstruction serves as a marker for increased risk of mortality following transplantation [9–11]. Risk factors for the development of PFT abnormalities following BMT include smoking history, pretransplant pulmonary infection and viral infection in the early post-transplant period, older age, underlying disease, pre-transplant chemotherapy and conditioning regimen, graft-versus-host-disease (GVHD), and HLA-mismatch [9, 10, 12–26]. Respiratory muscle weakness due to GVHD-associated myositis has been described following allogeneic BMT and may rarely be a contributing factor to restrictive pulmonary function abnormalities [27–29]. Several studies have suggested that abnormal pulmonary function may be a risk factor for the subsequent development of pulmonary complications in BMT recipients [14, 30–34]. However, some investigators have reported conflicting data showing no

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significant association between baseline pulmonary function values and subsequent pulmonary complications or mortality [15, 26]. Moreover, there is considerable variability among published studies in the particular pulmonary parameters deemed to be predictive, the post-transplant complications that they predict, and the strength of the association [35].

7.3 Asthma There are case reports of asthma developing after allogeneic BMT [36–40]. Limited data suggest that the serum IgE level, of donor origin, is elevated following transplantation [41]. Allergen-specific IgE-mediated hypersensitivity can be transferred from donor to recipient by B cells with allergen-specific memory leading to atopic dermatitis, allergic rhinitis, and asthma [36, 37, 41, 42]. The management of asthma in BMT recipients is similar to that of the other population.

B. Afessa

pulmonary complications are common in BMT recipients with GVHD. The pulmonary histology of BMT recipients with GVHD may show diffuse alveolar damage, lymphocytic bronchitis/ bronchiolitis with interstitial pneumonitis, bronchiolitis obliterans organizing pneumonia (BOOP), and bronchiolitis obliterans (BO) [45]. BO is a nonspecific inflammatory injury affecting primarily the small airways, often sparing the interstitium [46]. The term bronchiolitis obliterans has been used to describe a heterogeneous group of conditions [47]. This has been well depicted by Dr. Bergeron and colleagues in this book (see the Pearls section). In the clinical literature, it has been used to describe various conditions that result in airflow limitation. Philit et al. have recommended the term “post-transplant obstructive lung disease” instead of “bronchiolitis obliterans” because it takes into account both the functional definition and the clinical context of the syndrome [48]. Although BO can be idiopathic, it is often associated with connective tissue disease, inhaled toxins, infections, drugs, and chronic GVHD [46]. In the BMT recipient, BO is in most cases considered to be a severe manifestation of chronic GVHD, though infection and drug toxicity may be contributing factors [49].

7.4 Acute Pulmonary Edema Acute pulmonary edema in BMT recipients commonly occurs during the neutropenic phase and results from a combination of both hydrostatic and non-hydrostatic (capillary leak) factors [43]. Hydrostatic pulmonary edema may result from high volumes of fluid for medications, total parenteral nutrition, and multiple transfusions. The heart may also be compromised by a number of chemotherapeutic drugs, such as adriamycin and high-dose cyclophosphamide. Clinical features include weight gain, dyspnea, and bibasilar crackles. The radiographic findings may include vascular redistribution, increased interstitial markings, Kerley B lines, and ground-glass opacities. Cardiomegaly is generally absent unless there is associated cardiac dysfunction. Acute pulmonary edema can be prevented and treated with fluid restriction and diuretics.

7.5 Bronchiolitis Obliterans Graft-versus-host disease (GVHD) is a major complication of allogeneic BMT, with an overall incidence between 30% and 60% [44]. Infectious and non-infectious

7.5.1 Incidence and Risk Factors Airway disease as a complication of BMT was first recognized in the early 1980s [50]. BO almost exclusively affects allogeneic recipients with GVHD. There are only rare case reports of BO in autologous recipients [51]. In a study of 1,789 allogeneic BMT recipients, 47 (2.6%) developed BO compared to none of the 1,070 autologous recipients [52]. The reported incidence of BO varies among studies, related in part to patient population, and to variable definitions and diagnostic criteria. Although some studies have included pathologic findings, most of the reported cases of BO were defined by the presence of airflow limitation in the appropriate clinical setting. The frequency of BO was 3.9% among 4,180 allogeneic BMT recipients reported in 13 studies [53]. A recent study employing a highly sensitive definition of airflow obstruction documented an incidence of 26% [10]. The incidence varies between 6% and 35% in long-term survivors with GVHD [13, 49, 52, 54, 55]. GVHD, older donor and recipient age, methotrexate use, antecedent respiratory infection, and serum

7  Noninfectious Pulmonary Involvement in Hematopoietic Stem Cell or Bone Marrow Transplant Recipients

immunoglobulin deficiency are risk factors for BO [10, 13, 17, 49, 52, 56]. Patients who receive allogeneic T-cell depleted stem cells or are treated with a non-myeloablative conditioning regimen have a lower incidence of pulmonary complications, including BO [57, 58]. Although pulmonary infections are identified in many patients with BO, it is not clear whether they are directly related to airway disease or whether they result from immune suppression.

7.5.2 Pathogenesis The pathogenesis of BO in BMT recipients is not well understood. The association between BO and chronic GVHD suggests that host bronchiolar epithelial cells serve as a target for donor cytotoxic T-lymphocytes [59]. Recurrent aspiration of oral material due to esophagitis associated with GVHD, abnormal local immunoglobulin secretory function in the lungs, and unrecognized infections may also play roles [49, 59]. The variations in histopathology, bronchoalveolar lavage cellular composition, and clinical course; the frequency of associated pulmonary infection; the increased risk associated with methotrexate and the rare occurrence after autologous BMT suggest multi-factorial pathogenesis [51, 52, 59, 60].

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to exclude infection and complications of GVHD [59]. Since there is a high prevalence of sinusitis in allogeneic BMT recipients with GVHD, radiographic assessment of the paranasal sinuses is also recommended [59, 62–65]. If gastrointestinal GVHD or aspiration is a consideration, esophageal studies should be performed [59, 66]. PFT is the mainstay of diagnosis of BO [67]. Although normal airflow has been reported in BMT recipients with histologically proven BO [51], irreversible airflow obstruction is the hallmark of clinically significant disease. In lung transplant recipients, BO is classified based on spirometry into stage1 (FEV1 66–80% of peak post-transplant baseline), stage 2 (FEV1 51–65% of baseline) and stage 3 (FEV1 < 51% of baseline) [68]. The utility of this classification scheme in defining the severity or prognosis in BMT recipients has not been established. The chest radiograph is usually normal or may show hyperinflation. High-resolution computed tomography (HRCT) of the chest may show decreased lung attenuation, segmental or subsegmental bronchial dilatation, diminution of peripheral vascularity, centrilobular nodules, and expiratory air trapping (Fig. 7.2) [16, 48, 69, 70]. The most common finding on HRCT of the chest is decreased lung attenuation. The decreased lung attenuation and bronchial dilatations are more frequent and extensive in the lower lobes [69].

7.5.3 Clinical Findings and Diagnostic Evaluation BO can occur 2 months to 9 years after transplantation [17, 52, 55, 56, 61]. The majority of patients with BO present insidiously with dry cough and dyspnea, 40% develop wheezing, and 20% report antecedent “cold” symptoms; fever is notably absent [55, 56]. Twenty percent of the patients with BO had no respiratory symptoms at the time of the abnormal pulmonary function testing. Since the presenting respiratory symptoms are non-specific, a complete history, including prior medications and infections, and thorough physical examination focusing on signs of chronic GVHD should be obtained. Appropriate microbiology studies and laboratory evaluations, including complete blood count with differential, blood urea nitrogen, creatinine, total bilirubin, hepatic transaminases, gammaglobulin levels and subclasses, and urinalysis, are recommended

Fig. 7.2  Computed tomography of the chest in a patient with bronchiolitis obliterans showing diffuse areas of parenchymal hypoattenuation, proximal bronchiectasis, and subsegemental bronchial dilatation (Reprinted by permission from Afessa et al. [53], Copyright 2001 Macmillan Publishers Ltd.)

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Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) is used in BMT recipients with suspected BO mainly to exclude infection as the cause of airflow obstruction. Because BO involves the respiratory and membranous bronchioles and is patchy in distribution, transbronchial lung biopsy rarely demonstrates the characteristic histological changes and is consequently of limited utility. Furthermore, transbronchial lung biopsy is contraindicated in the presence of severe airways obstruction or thrombocytopenia. BAL shows neutrophilic and/or lymphocytic inflammation, but this is a non-specific finding [60, 71]. Video-assisted thoracoscopic lung biopsy is required to make a definitive histologic diagnosis. Lung biopsies show small airway involvement with fibrinous obliteration of the lumen with or without associated interstitial pneumonia, fibrosis, or diffuse alveolar damage (Fig. 7.3) [48, 55, 72–74]. Necrotizing bronchitis and bronchiolitis have been reported [72]. The inflammatory cellular infiltrates are usually peribronchiolar and consist of neutrophils and lymphocytes in varying proportions [75]. Surgical biopsies are rarely indicated since the diagnosis usually can be made on clinical grounds. The diagnostic criteria for BO in BMT recipients have not been clearly defined. Obstructive airways disease and BO may exist as distinct clinical entities in BMT recipients. Bronchiolitis may occur without airway obstruction [59], and, conversely, airflow obstruction can occur for a number of

Fig. 7.3  Lung pathology in bronchiolitis obliterans showing bronchiolar inflammation and luminal obliteration associated with excess fibrous connective tissue. Alveoli and their ducts are spared. (Hematoxylin and eosin and Verhoeff-Van Gieson elastic tissue stain.) (Reprinted by permission from Afessa et al. [53], Copyright 2001 Macmillan Publishers Ltd.)

B. Afessa

reasons other than BO (e.g., asthma, pre-existent chronic obstructive pulmonary disease, viral bronchiolitis). BO is usually established by the presence of irreversible airflow obstruction and the exclusion of other causes of this functional abnormality. BO should be suspected in allogeneic BMT recipients, particularly those with chronic GVHD, who present with chronic cough, wheezing, dyspnea, or hypoxemia with a normal chest radiograph and no evidence of respiratory infection [53, 59]. Similarly, the diagnosis should be considered in asymptomatic patients with new onset of airflow obstruction on screening spirometry. Other chronic diseases such as pulmonary veno-occlusive disease and early diffuse interstitial disease can present with similar signs and symptoms. However, pulmonary veno-occlusive disease is rare and unlikely to show airflow obstruction. Interstitial lung disease is typically associated with a restrictive defect on pulmonary function testing and parenchymal abnormalities on HRCT of the chest.

7.5.4 Treatment The treatment of BO in the BMT recipient is empiric, and typically consists of corticosteroids and augmented immunosuppression, targeting chronic GVHD. However, only a minority of the patients shows clinical

7  Noninfectious Pulmonary Involvement in Hematopoietic Stem Cell or Bone Marrow Transplant Recipients

improvement in response to treatment [52, 53]. Prednisone in a range of 1–1.5 mg kg−1 day−1 is typically given for 4–6 weeks [59]. If the respiratory status remains stable, corticosteroid therapy is tapered and discontinued over 6–12 months. If no improvement is noted within 1 month, or if deterioration continues, cyclosporin or azathioprine can be added [59]. Antithymocyte globulin and high-dose intravenous methylprednisolone have also been used with mixed results [52]. There is a case report of an allogeneic BMT recipient with BO whose pulmonary status improved following treatment with Imatinib mesylate, a specific tyrosine kinase inhibitor with antifibrinogenic properties [76]. Macrolide antibiotics are known to have antiinflammatory properties, and have been shown to improve symptoms, lung function, and mortality in patients with panbronchiolitis [77–83]. Additionally, there are recent reports of improved lung function in lung transplant recipients with bronchiolitis obliterans syndrome who received macrolide therapy [84, 85]. Currently, there is only one published study examining the effects of macrolides in BMT recipients with BO. Khalid and colleagues reported on eight BMT recipients with BO who were given azithromycin at an initial dose of 500 mg daily for 3 days followed by 250 mg three times weekly [86]. All patients demonstrated improvement in spirometric parameters, with a mean improvement in FEV1 of 20.6% (range 7.3–42.9%). This preliminary evidence, coupled with the lack of significant adverse effects, makes macrolide therapy an attractive therapeutic option, but validation with a prospective, randomized trial is necessary before this approach can be strongly endorsed. Although there are case reports suggesting beneficial response to thalidomide in BMT recipients with BO, a recent study showed no benefit [52, 87, 88]. While hypogammaglobulinemia has been described as a risk factor for chronic GVHD, prophylaxis with intravenous immunoglobulin has not been shown to prevent BO [89]. Cyclosporin may play a protective role against BO, but its role in established BO is unproven [90]. A randomized clinical trial showed inhaled corticosteroids to be ineffective in lung transplant recipients with bronchiolitis obliterans syndrome, and there is no reason to suspect that this intervention would be any more efficacious when applied to postBMT BO [91].

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In addition to immunosuppression and anti-inflammatory therapy, adjunctive treatments are important in the management of BMT recipients with BO. Prophylaxis for Pneumocystis jiroveccii pneumonia and Streptococcus pneumoniae should be maintained. Since bacterial infections, especially sinusitis, are common in patients with BO, they should be treated aggressively. Bronchodilator therapy is recommended, although only a minority of patients responds [56, 63, 72]. In selected BMT recipients with respiratory failure secondary to BO who were deemed to be cured of the underlying malignancy for which BMT was performed, lung transplantation is an option [45, 92–95].

7.5.5 Clinical Course Serial pulmonary function tests in allogeneic BMT recipients with BO have shown that the rate of decline in FEV1 is widely variable [56]. Deterioration in FEV1 correlates with increased mortality rate [56]. The FEV1 improves in only 8–20% [55, 59, 67, 70]. The reported case fatality rates vary widely, ranging from 14% to 100%, with an average case fatality rate of 59% [96]. In one study published 2 decades ago, the 3-year mortality rate of 35 allogeneic BMT recipients with GVHD and obstructive airway disease was 65% compared to 44% for those with GVHD without obstructive airway disease [56]. In a more recent study, the 5-year survival rate of 47 BMT recipients with BO was 10% compared to 40% for those without BO, highlighting the lack of progress in the management of BO over the last 2 decades [52].

7.6 Bronchiolitis Obliterans Organizing Pneumonia (BOOP) 7.6.1 Incidence and Pathogenesis BOOP is an uncommon lung disease characterized by the presence of granulation tissue within the terminal and respiratory bronchioles, the alveolar ducts, and alveoli. It was first described as a distinct clinical entity in 1985 [97]. BOOP can be either idiopathic or

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associated with other conditions such as infections, drugs, radiation, or connective tissue diseases [98]. The first cases of BOOP in BMT recipients were reported in the early 1990s [99, 100]. BOOP is not as common as BO in BMT recipients. In a report of 296 patients with BOOP from 63 publications, BMT recipients accounted for four (1.4%) [101]. At Vancouver General Hospital, 5 of the 25 (20%) patients identified as having BOOP over an 8-year period were allogeneic BMT recipients [101]. At the author’s institution, the incidence of BOOP was 1.7% among 179 allogeneic BMT recipients who survived for 3 months or longer [70]. The published medical literature on BOOP in BMT recipients is limited to case reports, with a maximum number of five patients [45, 70, 99–107]. Idiopathic BOOP is an inflammatory lung disease of unknown etiology [98]. Its occurrence almost exclusively in allogeneic recipients with GVHD suggests that it may represent a form of alloimmune injury to the lung by the transplanted stem cell [101]. BOOP is uncommon in BMT recipients treated with T-cell lymphocyte-depleted stem cells, highlighting the role T-cell lymphocytes may play in its pathogenesis [57, 108]. The higher frequency of human leukocyte antigen (HLA) B35 in BMT recipients with BOOP, compared to those without BOOP, suggests HLA B35 may play a role in its pathogenesis [109]. The exhaled nitric oxide level is increased in allogeneic BMT recipients with BOOP [104]. The rare occurrence of BOOP in autologous recipients suggests that other mechanisms may be involved as well [102]. A case report of BOOP associated with human herpes virus-6 in a BMT recipient suggests unrecognized infections may play role [110].

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disease is usually bilateral, it can be unilateral [102]. Pulmonary function tests usually show a restrictive defect, decreased DLCO, and normal flow rates [99, 101, 104, 112]. Arterial blood gas analysis may reveal mild hypoxemia [101]. Chest radiographs and computed tomography show patchy air space consolidation, ground-glass attenuation, and nodular opacities [99–101, 104, 113, 114]. The radiographic abnormalities usually have a peripheral distribution [115]. One recent study demonstrated increased exhaled nitric oxide concentration in BMT recipients with BOOP that decreases with response to treatment [104]. Although pulmonary function test and CT scan findings in conjunction with the clinical features may suggest the diagnosis, confirmation requires either surgical or transbronchial lung biopsy. Although the diagnosis of BOOP in the BMT recipient occasionally can be made with transbronchial lung biopsy in the appropriate clinical setting, about 85% of the patients require surgical lung biopsy [101]. Histologic confirmation of the diagnosis is particularly warranted before the patient is subjected to long-term corticosteroid therapy. Surgical lung biopsy, usually via video-assisted thoracoscopy, is considered the gold standard for the diagnosis of BOOP. The histologic hallmark of BOOP is the presence of patchy intraluminal fibrosis, consisting of polypoid plugs of immature fibroblast tissue resembling granulation tissue obliterating the distal airways, alveolar ducts, and peribronchial alveolar space (Fig. 7.4) [47].

7.6.2 Clinical Presentation and Diagnostic Evaluation The onset of BOOP is usually 1 month to 2 years after transplant [70, 99–101, 103–107, 111]. The presenting symptoms of BOOP include dry cough, dyspnea, and fever. Rarely, the disease may be asymptomatic [70]. Physical examination may reveal inspiratory crackles. BOOP should be included in the differential diagnosis of airspace disease in BMT recipients not responding to antibiotics. Although the airspace

Fig. 7.4  Lung pathology in bronchiolitis obliterans organizing pneumonia showing the presence of intraluminal granulation tissue in bronchioli, alveolar ducts, and alveoli. There is also interstitial infiltration with mononuclear cells and foamy macrophages. (Hematoxylin and eosin stain.) (Reprinted by permission from Afessa et al. [53], Copyright 2001 Macmillan Publishers Ltd.)

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7.6.3 Treatment and Prognosis Corticosteroid therapy is the treatment of choice for symptomatic patients with BOOP [70, 98–101, 104]. About 80% of BMT recipients with BOOP respond favorably to treatment [70, 99–101, 103–106, 111]. The duration and dosage of corticosteroid therapy in the BMT recipient with BOOP have not been clearly defined. Based on the experience from other patients, the initial dose of prednisone is in the range of 0.75–1.5 mg kg−1 day−1 to a maximum daily dose of 100 mg, administered for 1–3 months, then 40 mg/day for 3 months, and then 10–20 mg/day or every other day for a total of 1 year [98, 116]. Radiographic abnormalities usually clear within 1–3 months of initiating corticosteroid therapy [100, 101, 104, 105]. Erythromycin 10 mg kg−1 day−1 for 14 months has been used in conjunction with corticosteroid to treat BOOP in one allogeneic BMT recipient [103]. The case fatality rate of treated BOOP is 7.9% in the general population, but appears to be higher in BMT recipients [101]. Among 27 BMT recipients with BOOP documented in the literature, the overall case fatality rate was 19% [45, 70, 99–107, 111].

7.7 Idiopathic Pneumonia Syndrome (IPS) 7.7.1 Epidemiology IPS is characterized by clinical features of pneumonia and diffuse lung injury in the absence of an identified infection. The overall frequency of IPS is 10%, with a reported range of 2–17% [53, 117, 118]. Its median time of onset is between 21 and 87 days after transplant. Risk factors for IPS include old age, transplant for malignancy other than leukemia, pre-transplant chemotherapy, total body irradiation, GVHD, and positive donor cytomegalovirus serology [53].

7.7.2 Clinical Findings and Diagnostic Evaluation IPS is defined by the presence of widespread alveolar injury in the absence of lower respiratory tract

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infection characterized by the presence of acute, bilateral pulmonary infiltrates, associated symptoms of cough and dyspnea, hypoxemia, and restrictive physiology, in the absence of infection or heart failure [119]. The pathogenesis is not well defined [120–122]. Lung tissue injury, inflammation, and cytokine release are implicated. The clinical spectrum of IPS is broad, ranging from acute respiratory failure to incidental radiographic abnormalities [119]. The usual presentations include dyspnea, dry cough, hypoxemia, and non-lobar infiltrates [119]. Because IPS mimics infectious pneumonia, the majority of the patients are on antibiotics at the time of diagnosis [123]. Infection is excluded by the absence of a pathogen in BAL fluid and by the lack of clinical response to antimicrobial therapy. Diffuse alveolar hemorrhage (DAH) and peri-engraftment respiratory syndrome (PERDS) also fulfill the diagnostic criteria of IPS [124, 125]. Despite overlap in the clinical features of IPS, DAH, and PERDS, their responses to treatment and clinical courses are different [124]. In my diagnostic approach to patients with suspected IPS, I perform BAL and, if there are no contraindications, transbronchial lung biopsy. We proceed to video-assisted thoracoscopic lung biopsy if transbronchial lung biopsy is contraindicated or if the transbronchial specimen is inadequate. Lung biopsies of patients with IPS may show diffuse alveolar damage, organizing or acute pneumonia, and interstitial lymphocytic inflammation [6, 123].

7.7.3 Treatment There have been no randomized clinical trials addressing the treatment of IPS. Despite case reports of patients with IPS responding to treatment with corticosteroids, studies with larger sample sizes have not shown any outcome benefit [6, 123, 126]. Currently, management consists of supportive care and prevention and treatment of infection. There is a report of three cases of BMT recipients with IPS whose lung function improved following the administration of etanercept [122]. This observation awaits further confirmation by an ongoing clinical trial.

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7.7.4 Clinical Course and Prognosis The clinical course of BMT recipients with IPS is usually complicated by viral and fungal infections as well as pneumothorax, pneumomediastinum, subcutaneous emphysema, pulmonary fibrosis, and auto-immune polyserositis [53]. The overall mortality of IPS is 74%, with a reported range between 60% and 86% [53]. The 1-year survival rate is less than 15% [123, 126]. For those who require mechanical ventilation, the hospital mortality exceeds 95% [123].

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usually contraindicated because of thrombocytopenia. Surgical lung biopsy is rarely necessary, but may show diffuse alveolar damage [125].

7.9.3 Treatment and Prognosis High-dose corticosteroid therapy often leads to rapid clinical improvement [125]. Unlike DAH and IPS, only about one-third of BMT recipients with PERDS require ICU admission and mechanical ventilation [125]. The reported mortality rate of PERDS is about 26% [125].

7.8 Diffuse Alveolar Hemorrhage (DAH) DAH is discussed in Chap. 3.

7.10 Delayed Pulmonary Toxicity Syndrome (DPTS)

7.9 Periengraftment Respiratory Distress Syndrome (PERDS)

Chemotherapeutic agents and radiation therapy have been associated with pulmonary toxicities that manifest weeks to years later [130, 131]. In the 1990s, many patients with breast cancer were treated with a high-dose chemotherapy regimen consisting of cyclophosphamide, cisplatin, and bischloroethylinitrosurea (BCNU), followed by autologous BMT [132]. Following transplant, a significant number of these patients developed pulmonary complications, one of the more common referred to as the delayed pulmonary toxicity syndrome (DPTS) [118, 133– 139]. DPTS develops in up to 72% of autologous BMT recipients who have received high-dose chemotherapy for breast cancer [134, 135, 140]. The relatively high frequency, low mortality, and good response to corticosteroid treatment distinguish DPTS from IPS [134, 138, 139, 141]. Because recent studies have not shown a survival benefit, the  use of autologous BMT following high-dose ­chemotherapy for breast cancer has declined [142, 143]. The pathogenesis of DPTS is not known. The depletion of reduced glutathione and impaired antioxidant defenses caused by cyclophosphamide and BCNU have been implicated [138]. One study showed no significant correlation between patient age, stage of breast cancer, chemotherapy regimen, chest wall radiotherapy, tobacco use, prior lung disease, or ­ baseline pulmonary function and the development of DPTS [140].

7.9.1 Epidemiology PERDS occurs in approximately 5% of autologous BMT recipients [125]. About one-third of DAH occurs during the peri-engraftment period, and about onethird of patients with PERDS have DAH [125, 127].

7.9.2 Clinical Findings and Diagnostic Evaluation PERDS is a subset of IPS characterized by acute lung injury during the neutrophil peri-engraftment period. It represents the pulmonary component of the engraftment syndrome, which may also present with diarrhea and skin rash [125, 128, 129]. The diagnostic criteria of PERDS include the presence of fever and evidence of pulmonary injury in the form of hypoxia (arterial oxygen saturation <90%) and/or pulmonary infiltrates on chest radiograph, in the absence of cardiac dysfunction or infection, within 5 days of neutrophil engraftment [125]. The median time to onset of PERDS is 11 days (range, 4–25 days) after transplant [125]. BAL in patients with PERDS may show neutrophilic alveolitis [125]. Transbronchial lung biopsy is

7  Noninfectious Pulmonary Involvement in Hematopoietic Stem Cell or Bone Marrow Transplant Recipients

7.10.1 Clinical Findings and Diagnostic Evaluation Patients with DPTS present with cough, dyspnea, and fever [135, 139, 140]. The onset of symptoms ranges from 2 weeks to 4 months following transplantation [139, 140]. In the context of prior breast cancer treated with high-dose chemotherapy and autologous BMT, DPTS is diagnosed by demonstration of a decline in DLCO and exclusion of infectious causes [139, 140]. The DLCO declines in over 70% of patients with breast cancer treated with high-dose chemotherapy and autologous BMT [136]. In patients with DPTS, the median absolute DLCO decrement is 26% (range, 10–73%), and a nadir is reached in 15–18 weeks following transplant [139, 140]. The most common findings on CT of the chest are groundglass opacities [139]. Other abnormalities include linear or nodular opacities and consolidation. Many patients may have a normal chest CT at the onset of DPTS [139]. Because of the typical clinical presentation and response to therapy, invasive procedures such as bronchoscopy are rarely required [134, 135, 139, 140].

7.10.2 Treatment and Prognosis Corticosteroid therapy for DPTS usually results in resolution of symptoms and improvement in DLCO without long-term pulmonary sequelae [135, 139, 140]. Treatment usually consists of prednisone initiated at a dose of 60 mg/day for 14 days and subsequently tapered over 5–7 weeks [134]. While patients are being treated with steroids, they should also receive oral trimethoprim-sulfamethoxazole or aerosolized pentamidine prophylaxis against Pneumocystis jiroveccii pneumonia [134, 140]. One case of DPTS refractory to steroid was treated successfully with interferon-gamma [144]. A study using prophylactic inhaled fluticasone propionate 880 mg every 12 h for 12 weeks starting from the day of high-dose chemotherapy demonstrated a reduction in the frequency of DPTS to 35% compared to 73% in historical controls [145]. No deaths attributable to DPTS have been reported [134, 135, 139, 140]. The 3-year survival of stage II and III breast cancer patients who developed DPTS is 84%, which is not significantly different from those of patients who did not develop DPTS [140].

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7.11 Pulmonary Cytolytic Thrombi (PCT) Pulmonary cytolytic thrombi (PCT) is a non-infectious pulmonary complication of unknown etiology. Among BMT recipients, PCT occurs exclusively after allogeneic procedures, typically in the setting of GVHD. PCT has also been described at autopsy in a non-transplant patient who died following hip replacement surgery [146]. All except 1 of the 16 BMT recipients with PCT reported in the medical literature are from a single institution [147, 148]. Fifteen of the 16 patients were under age 18 years at the time of diagnosis [147, 148]. Despite the seemingly rare and previously unrecognized nature of PCT, it was found in 15 of 33 (45%) BMT recipients who underwent surgical lung biopsy for diagnosis of pulmonary nodules at the University of Minnesota [147].

7.11.1 Pathogenesis The pathogenesis of PCT is not known. Although the hemorrhagic infarcts in PCT are similar to those seen in angioinvasive fungal infections, none of the lung biopsies in the reported PCT cases had evidence of infection [147, 148]. The development of PCT exclusively in allogeneic BMT, and chiefly in those with GVHD, suggests that it may be a manifestation of GVHD targeting the endothelium of the lungs [147]. Demonstration of clinical and radiological improvement following increased immunosuppression also favors GVHD as the underlying pathogenic mechanism [147, 148].

7.11.2 Clinical Findings and Diagnostic Evaluation Most BMT recipients with PCT have active GVHD at the time of presentation [148–150]. The onset of PCT is between 8 and 343 days (median 72) after transplantation [148–150]. All patients are febrile, and some have cough at presentation [148–150]. Dyspnea has not been reported at presentation. Chest radiographs, usually performed as part of the evaluation of persistent fever, may be normal in 25% of the patients with PCT [150]. Abnormal chest radiographic findings include nodules, interstitial prominence, and atelectasis [150]. Chest CT shows multiple

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peripheral pulmonary nodules, ranging from a few millimeters to 4 cm in size. In one study, pleural effusion was reported in 1 of 13 patients who had undergone chest CT examination [150]. Bronchoscopy with bronchoalveolar lavage is used to exclude infection. Because of the peripheral and intravascular location of the nodules in PCT, transbronchial lung biopsy is unlikely to yield a diagnosis. Histological demonstration of PCT requires surgical lung biopsy or necropsy [148, 150]. The histologic features of PCT include occlusive vascular lesions and hemorrhagic infarcts due to thrombi that consist of intensely basophilic, amorphous material that may extend into the adjacent tissue through the vascular wall [147]. The amorphous material suggests cellular breakdown products [149]. Immunohistochemical studies show a discontinuous endothelial cell layer.

7.11.3 Treatment and Prognosis Because of the unclear etiology of PCT and concerns about an infectious cause of lung nodules, patients have been treated with broad-spectrum antibiotics, antifungals, and systemic corticosteroids [150]. In one recent case report, treatment with intravenous methylprednisolone 2 mg kg−1 day−1 and cyclosporin 3 mg/kg three times daily for 1 week followed by oral prednisone 30 mg/day and 125 mg cyclosporin twice daily resulted in improvement [148]. Although it is unclear which of these various interventions is actually beneficial, most of the patients with PCT described in the literature improved clinically within 1–2 weeks and radiographically over weeks to months [150]. There has been no reported death attributed to PCT [147, 148]. Of the 15 BMT recipients with PCT reported from the University of Minnesota, 10 were still alive at an average of 13 months after diagnosis and 5 died, 1 from GVHD and 4 from infectious complications [147]. The one patient reported from Mayo Clinic died of progressive pulmonary hypertension 4 months after the diagnosis of PCT, with no evidence of PCT at autopsy [148].

7.12 Pulmonary Veno-Occlusive Disease (PVOD) PVOD is a rare cause of pulmonary hypertension that has been associated with various conditions including BMT. Pulmonary hypertension in PVOD results from

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intimal fibrosis obstructing the pulmonary veins and venules. The incidence of PVOD in BMT recipients is not known. Wingard et  al. reported PVOD in 19 of 154 autopsies of allogeneic BMT recipients (12%) [151]. However, in a recent autopsy review of 71 adult BMT recipients from the Mayo Clinic (39 allogeneic), we did not identify any case of PVOD [152]. PVOD affects both genders. There are about 28 cases of BMT recipients with PVOD in the published literature [148, 151, 153–159]. The predominant underlying disease in BMT recipients with PVOD is hematologic malignancy. However, PVOD has been found following BMT for neuroblastoma and aplastic anemia [148, 157]. Only 2 of the 28 BMT recipients with PVOD had autologous grafts [155, 157]. The frequency of PVOD is particularly high in allogeneic BMT recipients who have concurrent interstitial pneumonia and hepatic veno-occlusive disease [151]. PVOD has been reported at autopsy following resolution of PCT [148].

7.12.1 Pathogenesis Since the reported cases of BMT recipients with PVOD are limited in scope and number, its etiology is not well defined. Infection, radiation, and chemotherapy are hypothesized to be contributing factors for the development of PVOD [153–155, 157, 160–162]. BCNU, mitomycin C, and bleomycin are among the chemotherapeutic agents implicated as potential causes of vascular injury [160, 162–165].

7.12.2 Clinical Findings and Diagnostic Evaluation Presenting symptoms are non-specific and include dyspnea, lethargy, and chronic cough [162]. As the pulmonary hypertension worsens, orthopnea, cyanosis, chest pain, abdominal pain due to hepatic congestion, and exertional syncope may be noted. Physical examination is also nonspecific and may reveal bibasilar crackles and inspiratory squeaks on auscultation of the lungs and findings indicative of pulmonary hypertension including right ventricular heave, loud pulmonic heart sound, lower extremity edema, and elevated jugular venous pressure [159]. Radiographic findings include Kerley B lines, prominent central pulmonary arteries, and scattered

7  Noninfectious Pulmonary Involvement in Hematopoietic Stem Cell or Bone Marrow Transplant Recipients

patchy opacities [159, 162]. Unlike other forms of primary pulmonary hypertension, pleural effusions are common in PVOD [162]. Echocardiogram and right heart catheterization show elevated pulmonary artery pressure. Pulmonary arteriogram may show delayed runoff and venous filling without arterial filling defects [159]. PFT demonstrates a decreased DLCO and restrictive ventilatory defect [159, 162, 166]. The triad of pulmonary arterial hypertension, radiographic evidence of pulmonary edema, and normal pulmonary artery occlusion pressure suggests PVOD. However, many patients with PVOD do not have this triad, and it is often difficult to get an accurate pulmonary artery occlusion pressure tracing in these patients [162]. The diagnosis cannot be made by bronchoscopy, although the findings of hemosiderosis and sclerosed venules in transbronchial lung biopsies suggest PVOD [158]. The definitive diagnosis of PVOD requires surgical lung biopsy. In the absence of this, most cases are diagnosed at postmortem examination [151, 157]. The pathologic hallmark of PVOD is the extensive and diffuse occlusion of pulmonary veins and venules by fibrous tissue [151, 162, 167].

7.12.3 Treatment and Prognosis There is no proven therapy for PVOD. Because observational trials involving patients with primary pulmonary hypertension have suggested improved survival in those treated with anticoagulation, some advocate treating PVOD with long-term warfarin [162]. There are case reports suggesting that steroids may be beneficial in BMT recipients with PVOD [153, 159]. However, the data supporting the use of steroid therapy and anticoagulation are limited to case reports [153, 159]. In one report of two BMT recipients with PVOD, methylprednisolone 2 mg/kg daily resulted in improvement of arterial oxygenation and dyspnea within 1–2 weeks [153]. In one of these two patients, discontinuation of steroid therapy led to recurrent disease that responded to additional treatment [153]. On the other hand, there are reports of BMT recipients with PVOD who deteriorated and died despite treatment with steroid therapy [155]. The role of vasodilators in PVOD is unclear. Despite case reports of successful therapy with oral vasodilators or intravenous administration of prostacyclin in PVOD, these agents can dilate the arterial vessels without concomitant venodilation, leading to increased transcapillary

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hydrostatic pressures, acute pulmonary edema, and death [162, 168]. Lung transplantation is a consideration in patients free of other comorbidities, including the underlying condition for which BMT was performed, but there is currently no published experience on outcomes of lung transplantation in this unique setting [161, 162]. In light of the limited treatment options and the generally progressive nature of the disease, it is not surprising that most patients with PVOD die within 2 years of diagnosis [162].

7.13 Other Pulmonary Complications 7.13.1 Pulmonary Arterial Hypertension Several cases of pulmonary arterial hypertension have been reported in BMT recipients [156, 169– 171]. The pathogenesis is not clearly defined. Normal pulmonary endothelium releases vasodilators, such as prostacyclin and endothelial-derived relaxing ­factors. Radiation- and chemotherapy-associated endothelial damage may be the mechanism for the development of the pulmonary hypertension [156, 169–171]. Prostacyclin infusion and calcium channel antagonists have been used for the treatment of pulmonary arterial hypertension in BMT recipients [169–171].

7.13.2 Pulmonary Alveolar Proteinosis Pulmonary alveolar proteinosis is characterized by excessive accumulation of surfactant lipoprotein in the alveoli leading to abnormal gas exchange [172]. The diagnosis of pulmonary alveolar proteinosis is made by the presence of periodic acid Schiff proteineceaous material in bronchoalveolar fluid [173]. Cordonnier et al. described three BMT recipients with pulmonary alveolar proteinosis [173]. All three had received allogeneic transplant for leukemia between 12 and 90 days before the onset of pulmonary symptoms. Chest radiographs showed diffuse infiltrates. The clinicians had suspected infection in two and alveolar hemorrhage in one. Only one of the three survived. A very didactical case of pulmonary alveolar proteinosis is depicted in this book by Drs. Vincent and Tandjaoui (see Pearl’s section).

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7.13.3 Chronic Eosinophilic Pneumonia Three cases of chronic eosinophilic pneumonia have been reported in BMT recipients, one autologous and two allogeneic [174–176]. Despite initial response to steroid therapy, one patient had a fatal course [174].

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7  Noninfectious Pulmonary Involvement in Hematopoietic Stem Cell or Bone Marrow Transplant Recipients 98. Epler GR (2001) Bronchiolitis obliterans organizing pneumonia. Arch Intern Med 161:158–164 99. Thirman MJ, Devine SM, O’Toole K et  al (1992) Bronchiolitis obliterans organizing pneumonia as a complication of allogeneic bone marrow transplantation. Bone Marrow Transplant 10:307–311 100. Mathew P, Bozeman P, Krance RA et al (1994) Bronchiolitis obliterans organizing pneumonia (BOOP) in children after allogeneic bone marrow transplantation. Bone Marrow Transplant 13:221–223 101. Alasaly K, Muller N, Ostrow DN et al (1995) Cryptogenic organizing pneumonia. A report of 25 cases and a review of the literature. Medicine (Baltimore) 74:201–211 102. Hayes-Jordan A, Benaim E, Richardson S et  al (2002) Open lung biopsy in pediatric bone marrow transplant patients. J Pediatr Surg 37:446–452 103. Ishii T, Manabe A, Ebihara Y et al (2000) Improvement in bronchiolitis obliterans organizing pneumonia in a child after allogeneic bone marrow transplantation by a combination of oral prednisolone and low dose erythromycin [In Process Citation]. Bone Marrow Transplant 26:907–910 104. Kanamori H, Fujisawa S, Tsuburai T et al (2002) Increased exhaled nitric oxide in bronchiolitis obliterans organizing pneumonia after allogeneic bone marrow transplantation. Transplantation 74:1356–1358 105. Kanda Y, Takahashi T, Imai Y et  al (1997) Bronchiolitis obliterans organizing pneumonia after syngeneic bone marrow transplantation for acute lymphoblastic leukemia. Bone Marrow Transplant 19:1251–1253 106. Kleinau I, Perez-Canto A, Schmid HJ et  al (1997) Bronchiolitis obliterans organizing pneumonia and chronic graft-versus-host disease in a child after allogeneic bone marrow transplantation. Bone Marrow Transplant 19: 841–844 107. Przepiorka D, Abu-Elmagd K, Huaringa A et  al (1993) Bronchiolitis obliterans organizing pneumonia in a BMT patient receiving FK506 [letter; comment]. Bone Marrow Transplant 11:502 108. Huisman C, van der Straaten HM, Canninga-van Dijk MR et al (2006) Pulmonary complications after T-cell-depleted allogeneic stem cell transplantation: low incidence and strong association with acute graft-versus-host disease. Bone Marrow Transplant 38:561–566 109. Yotsumoto S, Okada F, Yotsumoto S et  al (2007) Bronchiolitis obliterans organizing pneumonia after bone marrow transplantation: association with human leukocyte antigens. J Comput Assist Tomogr 31:132–137 110. Yata K, Nakajima M, Takemoto Y et al (2002) Pneumonitis with a bronchiolitis obliterans organizing pneumonia-like shadow in a patient with human herpes virus-6 viremia after allogeneic bone marrow transplantation. Kansen­ shogaku Zasshi 76:385–390 111. Baron FA, Hermanne JP, Dowlati A et al (1998) Bronchiolitis obliterans organizing pneumonia and ulcerative colitis after allogeneic bone marrow transplantation. Bone Marrow Transplant 21:951–954 112. Epler GR (1995) Bronchiolitis obliterans organizing pneumonia. Semin Respir Infect 10:65–77 113. Muller NL, Staples CA, Miller RR (1990) Bronchiolitis obliterans organizing pneumonia: CT features in 14 patients. AJR Am J Roentgenol 154:983–987

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114. Worthy SA, Flint JD, Muller NL (1997) Pulmonary complications after bone marrow transplantation: high-resolution CT and pathologic findings. Radiographics 17:1359–1371 115. Graham NJ, Muller NL, Miller RR et al (1991) Intrathoracic complications following allogeneic bone marrow transplantation: CT findings. Radiology 181:153–156 116. Cordier JF (2000) Organising pneumonia. Thorax 55:318–328 117. Chen CS, Boeckh M, Seidel K et al (2003) Incidence, risk factors, and mortality from pneumonia developing late after hematopoietic stem cell transplantation. Bone Marrow Transplant 32:515–522 118. Wong R, Rondon G, Saliba RM et  al (2003) Idiopathic pneumonia syndrome after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for high-risk breast cancer. Bone Marrow Transplant 31: 1157–1163 119. Clark JG, Hansen JA, Hertz MI et al (1993) NHLBI workshop summary. Idiopathic pneumonia syndrome after bone marrow transplantation. Am Rev Respir Dis 147: 1601–1606 120. Hauber HP, Mikkila A, Erich JM et  al (2002) TNFalpha, interleukin-10 and interleukin-18 expression in cells of the bronchoalveolar lavage in patients with pulmonary complications following bone marrow or peripheral stem cell transplantation: a preliminary study. Bone Marrow Transplant 30:485–490 121. Schots R, Kaufman L, Van RI et al (2003) Proinflammatory cytokines and their role in the development of major tran­ splant-related complications in the early phase after allo­ geneic bone marrow transplantation. Leukemia 17: 1150–1156 122. Yanik G, Hellerstedt B, Custer J et  al (2002) Etanercept (Enbrel) administration for idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 8:395–400 123. Kantrow SP, Hackman RC, Boeckh M et  al (1997) Idiopathic pneumonia syndrome: changing spectrum of lung injury after marrow transplantation. Transplantation 63:1079–1086 124. Afessa B, Tefferi A, Litzow MR et al (2002) Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 166:641–645 125. Capizzi SA, Kumar S, Huneke NE et  al (2001) Periengraftment respiratory distress syndrome during autologous hematopoietic stem cell transplantation. Bone Marrow Transplant 27:1299–1303 126. Crawford SW, Hackman RC (1993) Clinical course of idiopathic pneumonia after bone marrow transplantation. Am Rev Respir Dis 147:1393–1400 127. Afessa B, Tefferi A, Litzow MR et al (2002) Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 166: 1364–1368 128. Akasheh M, Eastwood D, Vesole DH (2003) Engraftment syndrome after autologous hematopoietic stem cell transplant supported by granulocyte-colony-stimulating factor (G-CSF) versus granulocyte-macrophage colony-stimulating factor (GM-CSF). Bone Marrow Transplant 31: 113–116

80 129. Maiolino A, Biasoli I, Lima J et al (2003) Engraftment syndrome following autologous hematopoietic stem cell transplantation: definition of diagnostic criteria. Bone Marrow Transplant 31:393–397 130. Abratt RP, Morgan GW, Silvestri G et al (2004) Pulmonary complications of radiation therapy. Clin Chest Med 25: 167–177 131. Limper AH (2004) Chemotherapy-induced lung disease. Clin Chest Med 25:53–64 132. Pedrazzoli P, Ferrante P, Kulekci A et al (2003) Autologous hematopoietic stem cell transplantation for breast cancer in Europe: critical evaluation of data from the European Group for Blood and Marrow Transplantation (EBMT) Registry 1990–1999. Bone Marrow Transplant 32: 489–494 133. Bearman SI, Overmoyer BA, Bolwell BJ et al (1997) Highdose chemotherapy with autologous peripheral blood progenitor cell support for primary breast cancer in patients with 4–9 involved axillary lymph nodes. Bone Marrow Transplant 20:931–937 134. Bhalla KS, Wilczynski SW, Abushamaa AM et  al (2000) Pulmonary toxicity of induction chemotherapy prior to standard or high- dose chemotherapy with autologous hematopoietic support. Am J Respir Crit Care Med 161:17–25 135. Chap L, Shpiner R, Levine M et al (1997) Pulmonary toxicity of high-dose chemotherapy for breast cancer: a noninvasive approach to diagnosis and treatment. Bone Marrow Transplant 20:1063–1067 136. Fanfulla F, Pedrazzoli P, Da Prada GA et  al (2000) Pulmonary function and complications following chemotherapy and stem cell support in breast cancer. Eur Respir J 15:56–61 137. Jones RB, Matthes S, Shpall EJ et  al (1993) Acute lung injury following treatment with high-dose cyclophosphamide, cisplatin, and carmustine: pharmacodynamic evaluation of carmustine. J Natl Cancer Inst 85:640–647 138. Todd NW, Peters WP, Ost AH et al (1993) Pulmonary drug toxicity in patients with primary breast cancer treated with high-dose combination chemotherapy and autologous bone marrow transplantation. Am Rev Respir Dis 147: 1264–1270 139. Wilczynski SW, Erasmus JJ, Petros WP et  al (1998) Delayed pulmonary toxicity syndrome following high-dose chemotherapy and bone marrow transplantation for breast cancer. Am J Respir Crit Care Med 157:565–573 140. Cao TM, Negrin RS, Stockerl-Goldstein KE et  al (2000) Pulmonary toxicity syndrome in breast cancer patients undergoing BCNU-containing high-dose chemotherapy and autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant 6:387–394 141. Peters WP, Ross M, Vredenburgh JJ et al (1993) High-dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. J Clin Oncol 11: 1132–1143 142. Report on state of the art in blood and marrow transplantation. IBMTR/ABMTR Newsletter 2003; 10:7–10 143. Stadtmauer EA, O’Neill A, Goldstein LJ et  al (2000) Conventional-dose chemotherapy compared with highdose chemotherapy plus autologous hematopoietic stemcell transplantation for metastatic breast cancer. Philadelphia

B. Afessa Bone Marrow Transplant Group. N Engl J Med 342: 1069–1076 144. Suratt BT, Lynch DA, Cool CD et  al (2003) Interferongamma for delayed pulmonary toxicity syndrome resistant to steroids. Bone Marrow Transplant 31:939–941 145. McGaughey DS, Nikcevich DA, Long GD et  al (2001) Inhaled steroids as prophylaxis for delayed pulmonary toxicity syndrome in breast cancer patients undergoing highdose chemotherapy and autologous stem cell transplantation. Biol Blood Marrow Transplant 7:274–278 146. Castellano-Sanchez AA, Poppiti RJ (2001) Pulmonary cytolytic thrombi (PCT). A previously unrecognized complication of bone marrow transplantation (BMT). Am J Surg Pathol 25:829–831 147. Gulbahce HE, Pambuccian SE, Jessurun J et  al (2004) Pulmonary nodular lesions in bone marrow transplant recipients: impact of histologic diagnosis on patient management and prognosis. Am J Clin Pathol 121:205–210 148. Morales IJ, Anderson PM, Tazelaar HD et al (2003) Pulmonary cytolytic thrombi: unusual complication of hematopoietic stem cell transplantation. J Pediatr Hematol Oncol 25:89–92 149. Gulbahce HE, Manivel JC, Jessurun J (2000) Pulmonary cytolytic thrombi: a previously unrecognized complication of bone marrow transplantation. Am J Surg Pathol 24: 1147–1152 150. Woodard JP, Gulbahce E, Shreve M et al (2000) Pulmonary cytolytic thrombi: a newly recognized complication of stem cell transplantation. Bone Marrow Transplant 25:293–300 151. Wingard JR, Mellits ED, Jones RJ et al (1989) Association of hepatic veno-occlusive disease with interstitial pneumonitis in bone marrow transplant recipients. Bone Marrow Transplant 4:685–689 152. Sharma S, Nadrous HF, Peters SG et al (2005) Pulmonary complications in adult blood and marrow transplant recipients: autopsy findings. Chest 128:1385–1392 153. Hackman RC, Madtes DK, Petersen FB et  al (1989) Pulmonary venoocclusive disease following bone marrow transplantation. Transplantation 47:989–992 154. Kuga T, Kohda K, Hirayama Y et  al (1996) Pulmonary veno-occlusive disease accompanied by microangiopathic hemolytic anemia 1 year after a second bone marrow transplantation for acute lymphoblastic leukemia. Int J Hematol 64:143–150 155. Salzman D, Adkins DR, Craig F et al (1996) Malignancyassociated pulmonary veno-occlusive disease: report of a case following autologous bone marrow transplantation and review. Bone Marrow Transplant 18:755–760 156. Seguchi M, Hirabayashi N, Fujii Y et al (2000) Pulmonary hypertension associated with pulmonary occlusive vasculopathy after allogeneic bone marrow transplantation. Transplantation 69:177–179 157. Trobaugh-Lotrario AD, Greffe B, Deterding R et al (2003) Pulmonary veno-occlusive disease after autologous bone marrow transplant in a child with stage IV neuroblastoma: case report and literature review. J Pediatr Hematol Oncol 25:405–409 158. Troussard X, Bernaudin JF, Cordonnier C et  al (1984) Pulmonary veno-occlusive disease after bone marrow transplantation. Thorax 39:956–957 159. Williams LM, Fussell S, Veith RW et al (1996) Pulmonary veno-occlusive disease in an adult following bone marrow

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8

Are There Any Pulmonary Issues Specifically Related to Cord Blood Transplants? Jonathan Gutman

Contents 8.1 Introduction............................................................. 83 8.2 Infusional Toxicities................................................ 83 8.3 Preengraftment Syndrome..................................... 84 8.4 Infections................................................................. 84 8.5 Pulmonary Immune Reactions.............................. 84 References............................................................................ 84

8.1 Introduction A growing body of evidence supports the efficacy of umbilical cord blood as a donor source for hematopoietic stem cell transplantation, and the number of cord blood transplants (CBTs) is increasing [1]. Among pediatric patients, data suggest that outcomes following CBT are comparable to outcomes following unrelated donor transplants and that outcomes following well-matched CBT may be superior to outcomes following matched unrelated donor transplants. For adult patients, data continue to accumulate demonstrating outcomes similar to unrelated donor transplants, but early transplant-related mortality (TRM) due to delayed engraftment, increased graft failures, and infectious complications remains an important challenge. Broadly speaking, CBT patients can be expected to have similar pulmonary complications as non-CBT patients, and there is no significant literature des­ cribing distinct patterns of pulmonary complications ­following CBT. Given the unique immunologic characteristics of cord blood, however, larger studies may demonstrate unique pulmonary complications following CBT, and several pulmonary issues specifically related to CBT are worthy of consideration. In this brief report, we highlight complications that have been reported or that are based on our experience in recipients of CBT.

8.2 Infusional Toxicities J. Gutman  Fred Hutchinson Cancer Research Center, Seattle, Washington, USA e-mail: [email protected]

Unlike matched sibling and unrelated donor transplants, where stem cell products are typically infused fresh, cord blood units are processed, frozen, and

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_8, © Springer-Verlag Berlin Heidelberg 2011

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stored for subsequent use. Cord blood banks use a variety of strategies to process units for storage, ranging from plasma depletion only to intensive red cell depletion. Transplant centers use a variety of techniques to process frozen units prior to infusion, ranging from bedside thaw and infusion to albumin dilution and infusion to wash and infusion. In the United States, the National Marrow Donor Program (NMDP) has recently issued a warning describing four cases of serious adverse events involving heart failure and acute pulmonary edema following the use of plasmadepleted, red blood cell-replete units that were not washed prior to infusion. Based on these findings, the NMDP recommends washing of cord blood units, particularly red blood cell-replete units, prior to infusion. Physicians should be aware of this potential pulmonary/cardiovascular complication [2]. Larger studies will better characterize the incidence and pathophysiology underlying this phenomenon.

8.3 Preengraftment Syndrome Following CBT, “preengraftment” syndrome has been reported to occur at an increased frequency as compared to related or unrelated donor transplant. The syndrome is being increasingly well characterized. It develops before or at the time of engraftment, and its clinical manifestations include high fever in the absence of infection as well as diffuse erythematous skin rash resembling acute graft-versus-host disease (aGVHD) and may include fluid retention. Those patients who experience fluid retention may develop pulmonary infilitrates. The syndrome frequently responds to a brief burst of steroids (common dosing 3 days of 1 mg/kg methylpredinsolone) and appears to be distinct from early onset acute GVHD. Some data suggest, however, the preengraftment syndrome may be predictive of the subsequent development of GVHD [3].

8.4 Infections Infectious complications, including pulmonary infections, are a significant concern following CBT [4, 5]. Delayed neutrophil engraftment exposes patients to

J. Gutman

prolonged vulnerability to bacterial and fungal infections [5]. Several series have reported high rates of early TRM following CBT, and pulmonary infections account for a portion of these early events. Delayed T-cell reconstitution following CBT raises concerns about prolonged and increased risk for viral infections [6], including respiratory infections [7, 8]. No large studies, however, have quantified the incidence of respiratory viral infections following CBT. Pulmonary physicians should have a high suspicion for infectious etiologies of pulmonary symptoms ­following CBT.

8.5 Pulmonary Immune Reactions In numerous studies, cord blood is associated with a lower incidence of chronic GVHD than transplant with unrelated donors. It is reasonable to speculate, therefore, that CBT may be associated with lower ­incidences of pulmonary transplant complications attributed to immune reactions between the donor and host [9]. The incidences of bronchiolitis obliterans (BO) and bronchiolitis obliterans organizing pneumonia (BOOP) may be lower following CBT [10, 11], but no studies to date have examined this outcome. In conclusion, although there is no sound evidence of increased incidence of respiratory events in recipients of CBTs, clinicians must be aware of some infectious or noninfectious conditions that may occur in CBT patients. Given the unique immunologic characteristics of cord blood, several pulmonary issues ­specifically related to CBT (infusional toxicity, preengraftment syndrome, pulmonary infections, and ­pulmonary immune reactions) are worthy of consideration.

References   1. Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R, Bosi A, Jacobsen N, Ruutu T, De Lima M, Finke J, Frassoni F, Gluckman E, Acute Leukemia Working Party of European Blood and Marrow Transplant Group, Eurocord-Netcord Registry (2004) Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med 351(22):2276–2285, 25 Nov 2004

8  Are There Any Pulmonary Issues Specifically Related to Cord Blood Transplants?   2. Konuma T, Ooi J, Takahashi S, Tomonari A, Tsukada N, Kobayashi T, Sato A, Kato S, Kasahara S, Ebihara Y, Nagamura-Inoue T, Tsuji K, Tojo A, Asano S (2008) Cardiovascular toxicity of cryopreserved cord blood cell infusion. Bone Marrow Transplant 41(10):861–865   3. Patel KJ, Rice RD, Hawke R, Abboud M, Heller G, Scaradavou A, Young JW, Barker JN (2010) Pre-engraftment syndrome after double-unit cord blood transplantation: a distinct syndrome not associated with acute graft-versushost disease. Biol Blood Marrow Transplant 16(3):435–440   4. Cahu X, Rialland F, Touzeau C, Chevallier P, Guillaume T, Delaunay J, Ayari S, Dubruille V, Le Gouill S, Mahe B, Gastinne T, Blin N, Saulquin B, Harousseau JL, Moreau P, Mohty M (2009) Infectious complications after unrelated umbilical cord blood transplantation in adult patients with hematologic malignancies. Biol Blood Marrow Transplant 15(12):1531–1537   5. Szabolcs P, Cairo MS (2010) Unrelated umbilical cord blood transplantation and immune reconstitution. Semin Hematol 47(1):22–36   6. Montesinos P, Sanz J, Cantero S, Lorenzo I, Martín G, Saavedra S, Palau J, Romero M, Montava A, Senent L, Martínez J, Jarque I, Salavert M, Córdoba J, Gómez L, Weiss S, Moscardó F, De la Rubia J, Larrea L, Sanz MA, Sanz GF (2009) Incidence, risk factors, and outcome of cytomegalovirus infection and disease in patients receiving prophylaxis with oral valganciclovir or intravenous ganciclovir after umbilical cord blood transplantation. Biol Blood Marrow Transplant 15(6):730–740, Epub 2009, Apr 11

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  7. Almyroudis NG, Fabian J, Hahn T, Segal BH, Wetzler M, McCarthy PL Jr (2009) Late infectious complications after cord blood stem cell transplantation. Eur J Clin Microbiol Infect Dis 28(11):1405–1408   8. Yazaki M, Atsuta Y, Kato K, Kato S, Taniguchi S, Takahashi S, Ogawa H, Kouzai Y, Kobayashi T, Inoue M, Kobayashi R, Nagamura-Inoue T, Azuma H, Takanashi M, Kai S, Nakabayashi M, Saito H, Japan Cord Blood Bank Network (2009) Incidence and risk factors of early bacterial infections after unrelated cord blood transplantation. Biol Blood Marrow Transplant 15(4):439–446   9. Shima T, Yoshimoto G, Miyamoto T, Yoshida S, Kamezaki K, Takenaka K, Iwasaki H, Harada N, Nagafuji K, Teshima T, Shimono N, Akashi K (2009) Disseminated tuberculosis following second unrelated cord blood transplantation for acute myelogenous leukemia. Transpl Infect Dis 11(1): 75–77 10. Gutman JA, Leisenring W, Appelbaum FR, Woolfrey AE, Delaney C (2009) Low relapse without excessive transplantrelated mortality following myeloablative cord blood transplantation for acute leukemia in complete remission: a matched cohort analysis. Biol Blood Marrow Transplant 15(9):1122–1129 11. Majhail NS, Parks K, Defor TE, Weisdorf DJ (2006) Diffuse alveolar hemorrhage and infection-associated alveolar hemorrhage following hematopoietic stem cell transplantation: related and high-risk clinical syndromes. Biol Blood Marrow Transplant 12(10):1038–1046

 

9

Cardiovascular Complications of Cancer Therapeutics Aarif Y. Khakoo and Callie S. Kwartler

Contents 9.1 Introduction............................................................. 87 9.2 Anthracyclines........................................................ 9.2.1 Genetic Risk............................................................. 9.2.2 Mechanistic Insights................................................. 9.2.3 Synergistic Interactions............................................ 9.2.4 Cardioprotective Strategies....................................... 9.2.5 Conclusions..............................................................

90 91 91 92 93 95

9.3 Mitoxantrone........................................................... 95 9.3.1 Mechanistic Insights................................................. 95 9.4 Tyrosine Kinase Inhibitors.................................... 96 9.4.1 Trastuzumab.............................................................. 96 9.4.2 Lapatinib................................................................... 97 9.4.3 Imatinib..................................................................... 97 9.4.4 Dasatinib and Nilotinib............................................. 98 9.4.5 Sunitinib.................................................................... 98 9.4.6 Sorafenib................................................................... 99 9.4.7 Bevacizumab............................................................. 99 9.4.8 Conclusions.............................................................. 100 9.5 Monoclonal Antibody Therapies........................... 100 9.5.1 Alemtuzumab............................................................ 100 9.5.2 Rituximab................................................................. 100 9.5.3 Cetuximab................................................................. 101

9.9 Other Chemotherapeutic Agents.......................... 102 9.9.1 Bleomycin................................................................. 102 9.9.2 Irinotecan.................................................................. 103 9.9.3 Cytarabine................................................................. 103 9.9.4 Gemcitabine.............................................................. 103 9.10 Microtubule-Altering Therapies........................... 103 9.10.1 Vinca Alkaloids........................................................ 103 9.10.2 Taxanes..................................................................... 104 9.11 Hormone Therapies................................................ 104 9.12 Other Miscellaneous Drugs.................................... 104 9.12.1 Bortezomib............................................................... 104 9.12.2 Thalidomide.............................................................. 105 9.12.3 Interferon-a.............................................................. 105 9.12.4 Arsenic Trioxide....................................................... 106 9.12.5 IL-2........................................................................... 106 9.13 Cardiotoxicity as a Discovery Platform................ 106 9.14 Conclusion............................................................... 107 References............................................................................ 108

9.1 Introduction

9.6 5-Fluorouracil and Capecitabine........................... 101 9.7 Cyclophosphamide.................................................. 101 9.8 Cisplatin and Cisplatin-Based Combination Therapies................................................................. 102 9.8.1 Toxicity with Combination Therapies...................... 102

A.Y. Khakoo () Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030 e-mail: [email protected] C.S. Kwartler Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX, 77030

As treatment for cancer has modernized and the number of anticancer drugs has multiplied, survival of cancer patients beyond their initial disease has improved dramatically. Perversely, the same agents that bring about a “cure” for cancer can also lead to devastating cardiovascular side effects, including cardiomyopathy, myocardial infarction, thromboembolism, hypertension, arrhythmias, and QT prolongation. In fact, cancer survivors are in many cases more likely to develop cardiovascular disease than experience a recurrence of their malignancy. Cardiovascular toxicities not only increase morbidity and mortality for these patients, but also impair the ability of clinicians to manage a patient’s anticancer regimen with maximal efficiency. This chapter provides

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_9, © Springer-Verlag Berlin Heidelberg 2011

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A.Y. Khakoo and C.S. Kwartler

Table 9.1  Cardiotoxic drugs by disease presentation Cardiomyopathy Drug Incidence

Notes

Anthracyclines (chronic)

4–26% [3, 6]

Symptomatic dilated cardiomyopathy or heart failure; irreversible

Mitoxantrone (chronic)

2.6% [54, 55]

Symptomatic heart failure; irreversible

Trastuzumab

1–10% [26, 63–65]

LV dysfunction in up to 10%, heart failure in 1–4%; reversible

Lapatinib

0.2–2% [66, 72]

LV dysfunction in 2%, symptomatic heart failure in 0.2%; reversible

Imatinib

1.7–4% [191, 192]

Symptomatic heart failure

Sunitinib

11–19% [86, 87]

LV dysfunction in 19%, grade 3 dysfunction or clinical heart failure in 7%

Cyclophosphamide

10–28% [110, 193]

Typically acute onset within 1–10 days of first dose

Mitomycin

Rare [54, 194]

Interferon a

Unknown [88]

Dilated cardiomyopathy; incidence suspected to be underreported due to similar symptoms with other complications

Gemcitabine

1.8% [136]

Cardiac dysfunction with decline in LVEF

Bortezomib

Up to 10% [163, 195]

Mostly based on case reports and one study that found a 10% incidence of heart failure serious enough to cause hospitalization

All-trans retinoic acid

17% [194]

Described as “substantial decline” in LVEF, symptomatic of “retinoic acid syndrome”

Thromboembolism Alemtuzumab

Rare [101, 196]

Controversial; events observed in some studies but not others

Cisplatin

Up to 12.9% [119, 120]

Includes DVT, PE, arterial thromboses, CVA, and angina pectoris; high risk of grade 4 or 5 events

Irinotecan

Up to 20% [131]

Both venous and arterial thromboembolic events

Oxaliplatin

1–2% [5]

Increased incidence (8%) when combined with capecitabine

Estramustine

Up to 10% [54]

Includes coronary ischemia, cerebrovascular ischemia, PE, and venous thromboembolism

Tamoxifen

1.2% [156, 197]

Includes DVT and PE

Thalidomide

12–20% [95, 167]

Includes lower extremity DVT and PE most commonly, but rarely stroke, unstable angina, and cerebral venous sinus thrombosis reported

Denileukin diftitox

11% [194]

Results from vascular leak syndrome

Bevacizumab

2–11% [5, 96, 97]

mostly arterial thromboembolism; includes CVA, angina, sudden death, and other manifestations

Sunitinib

17–47% [86, 198]

Any grade 47%, grade 3 or higher 17%

Sorafenib

“Common” [91]

Mechanistically similar to sunitinib, so incidence is likely similar

Bevacizumab

8–18% [96]

Grade 3 or higher hypertension 8–18%

Hypertension

9  Cardiovascular Complications of Cancer Therapeutics Table 9.1  (continued) Hypertension Drug

89

Incidence

Notes

Vinorelbine

Rare [145]

Based on case reports

Docetaxel

Unknown [5]

Can cause either hypo- or hypertension

Dasatinib

1% [78, 199]

Grade 3–4 QT prolongation

Nilotinib

3% [77–79]

Grade 3–4 QT prolongation

Arsenic trioxide

Up to 63% [169–172]

Can lead to tachyarrhythmias, torsades de pointes, or sudden death

Vorinostat

3.5–6% [194]

QT prolongation

Myocardial infarction Gefitinib

Rare [200]

Case reports only

Sorafenib

2.9% [92, 93]

Acute coronary symptoms including MI

Cisplatin

12.9% [116–118]

Ischemic disease; more common in elderly; possibly related to thromboembolic disease (see above)

Bleomycin

<3% [130]

Severe chest pain; rare ischemia or MI in young patients

Etoposide

Rare [194, 201]

Case reports only; rechallenge worsens cardiac function

Gemcitabine

Rare [137, 138]

Case reports only

Vinca alkaloids

1% [54, 144, 145]

5-Fluorouracil

4% [106]

Myocardial ischemia or infarction, likely due to coronary vasospasm

Capecitabine

<4% [108]

Similar to 5-fluorouracil

Aromatase inhibitors

1–2% [155, 202, 203]

Increased incidence relative to tamoxifen, but controversial as to whether incidence is increased relative to controls

IL2

More than 1.5% [176]

1.5% treatment-related deaths; MI and ischemia are more common

Pentostatin

Rare [194]

Case reports only; incidence increases when co-treated with cyclophosphamide

Methotrexate

Rare [54]

Case reports only

Anthracyclines (acute)

Rare [1, 5]

Transient ventricular arrhythmias

Mitoxantrone (acute)

Rare [54, 55]

Transient ventricular arrhythmias

Nilotinib

2% [79]

Alemtuzumab

Rare [101, 196]

Controversial; events observed in some studies but not in others

Rituximab

1–7% [204]

Various types of arrhythmias

Gemcitabine

2–3% [136, 139, 140]

Case reports of atrial fibrillation; grade 1–4 ventricular tachyarrhythmias in 2.3%

5-fluorouracil

>2.2% [105]

2.2% suffer cardiac death due to arrhythmias

Arrhythmias

(continued)

90 Table 9.1  (continued) Arrhythmias Drug

A.Y. Khakoo and C.S. Kwartler

Incidence

Notes

Paclitaxel

5% [146, 151]

Sinus bradycardia in up to 30%, more serious arrhythmias in 5%; typically transient

Docetaxel

Up to 5% [5]

Dysrhythmias or tachycardia

Bortezomib

Rare [163, 195]

Mostly case reports

Interferon a

Up to 20% [54, 168]

Supraventricular arrhythmias most common; can be lethal

IL-2

6% [54]

Homoharringtonine

Rare [194]

Most common presentation is hypotension; arrhythmias are rare

Pentostatin

Rare [194]

Case reports only; incidence increases when co-treated with cyclophosphamide

Methotrexate

Rare [54, 205]

Case reports only, no typical clinical presentation of arrhythmia

LV left ventricular, LVEF left ventricular ejection fraction, DVT deep venous thrombosis, PE pulmonary embolism, CVA cerebrovascular accident, MI myocardial infarction

an overview of the cardiovascular complications associated with specific anticancer drugs (see Table 9.1 for a list of effects categorized by disease presentation). We specifically focus on the drugs most strongly associated with cardiotoxicities, and present information on the risk factors, incidence, and specific mechanisms of the effect on the cardiovascular system.

9.2 Anthracyclines Anthracyclines are a class of drugs originally isolated from microorganisms that are used to treat a wide spectrum of cancers. Doxorubicin (also called adriamycin) and daunorubicin were the original anthracyclines, and are still the most potent antitumor drugs in the class [1]. Epirubicin, idarubicin, and others have since been developed in attempts to create a better anthracycline with more potent antitumor effects and less cardiotoxicity. Daunorubicin and idarubicin are typically used to treat acute lymphoblastic and myeloblastic leukemias, while doxorubicin and epirubicin are used to treat a broader spectrum of solid and hematological cancers [2]. The antitumor effects of anthracyclines are mediated by their DNA intercalating effects and inhibition of topoisomerase II [3]. The potency of the antitumor effect, however, is counterbalanced by a severe dose-

dependent toxic effect causing irreversible cardiomyopathy. However, cardiotoxicity may not be mediated through the same mechanisms as antineoplastic effects, and appears to be independent of tumor type [4]. There are four general categories of cardiotoxicity related to anthracyclines: acute (during or immediately after treatment), subchronic (within 1–3  days after treatment), early chronic (develops late in the treatment course or up to months after completion of treatment), and delayed or late-onset (manifests years to decades after therapy). Acute cardiotoxicity, which is not dosedependent, most frequently manifests as transient arrhythmias [5]. In rare cases, however, acute doxorubicin toxicity has been shown to cause acute heart failure with a decrease in left ventricular ejection fraction down to 10%. By contrast, subchronic cardiotoxicity is most frequently seen as a pericarditis-myocarditis syndrome, and the chronic and late-onset cardiotoxicities are usually characterized by dilated cardiomyopathy, which results in a decline in systolic or diastolic cardiac function and eventually congestive heart failure [6]. Delayed cardiotoxicity most frequently manifests in survivors of childhood cancer and can be particularly brought to the surface by stressors such as pregnancy. Risk factors contributing to the incidence of anthracycline cardiotoxicity include the extremes of age, preexisting cardiac disease, female gender, AfricanAmerican race, and trisomy 21. Use of certain other

9  Cardiovascular Complications of Cancer Therapeutics

chemotherapeutic agents or mediastinal radiation along with anthracyclines also increases risk [7]. These risk factors apply to both acute and all chronic types of cardiotoxicity [8]. However, the most significant (and in some studies the only independent) ­predictor of developing anthracycline-induced cardiomyopathy is cumulative dose. Dosing limits have been set for each drug above which the incidence of cardiotoxicity becomes unacceptably high: for doxorubicin dose is limited to 400–450  mg/m2, whereas for the modified anthracycline epirubicin the limiting dose is 750  mg/m2[5]. Even at these confined doses, reports cite incidences of chronic cardiotoxicity ranging from <4% to 26%. Studies have suggested that children respond differently to anthracyclines than adults, with possibly less risk of developing acute or chronic cardiomyopathy but significantly increasing risk with time from treatment of developing delayed cardiomyopathy. Indeed, one clinical trial that looked at 607 children found a cumulative incidence of anthracycline-induced heart failure of 2.8% 6.3 years after treatment, but that risk increased significantly up to 5% after 15 years of follow-up [9]. Longer follow-up times would likely yield even higher incidences of cardiac dysfunction in childhood cancer survivors treated with anthracyclines [4]. The cumulative dose above which incidence was significantly increased was also lower in children: only 300 mg/m2 of doxorubicin [8].

9.2.1 Genetic Risk Some recent work has shown that genetic factors influence the development of anthracycline cardiotoxicity. Strong support for a genetic role in determining risk originally came from knockout and transgenic animal studies that showed increased sensitivity or resistance to anthracyclines. For example, overexpression of the multi-drug resistance gene MDR1 is protective, while overexpression of the carbonyl reductase gene is sensitizing. In humans [10], higher incidences of anthracycline cardiotoxicity have been found associated not only with SNPs in NADPH oxidase, but also with polymorphisms in GSTP, a phase II detox enzyme, and CBR3, a paralog of the carbonyl reductase CBR1 [11]. One group sequenced candidate

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genes in patients who did or did not develop cardiotoxic responses to anthracycline therapy. They found significantly associated SNPs in multiple NADPH oxidase subunits, suggesting the importance of this protein complex in modulating risk of anthracycline cardiotoxicity. They also found that SNPs in three transmembrane efflux receptors responsible for transport of anthracyclines correlated strongly with acute cardiotoxic responses. Polymorphisms in adrenergic receptors and angiotensin-converting enzymes were not associated with increased cardiotoxicity [10]. With the sequencing of the human genome and the development of more advanced methods for genomewide association studies, continued research into this area could be crucial both to understanding the mechanisms and to predicting risk of individual patients. In the future, patients with alleles increasing their risk could be put on lower doses of anthracyclines or be treated with alternative drugs to decrease the overall incidence of cardiotoxicity substantially.

9.2.2 Mechanistic Insights Recent focus has been on determining mechanisms of cardiotoxicity in the hope of identifying possible cardioprotective mechanisms or deriving a new anthracycline that is less cardiotoxic but no less potent against tumors. Endomyocardial biopsies of affected hearts reveal characteristic ultrastructural features of anthracycline-induced cardiac damage. Cytoplasmic vacuolization, swelling of mitochondria, increased numbers of lysosomes, loss of myofibrils, and dilation of the sarcoplasmic reticulum are all frequently observed changes [12]. Treatment of cultured cardiomyocytes with anthracyclines induces an apoptosis-like cell death phenotype similar to that observed in the tissue [13]. Interference with multiple aspects of cardiomyocyte cellular function have been observed after exposure to anthracyclines, including effects on myocardial calcium handling [14], adrenergic receptor signaling [14], myocardial protein synthesis [15], and mitochondrial function [16]. In addition, multiple studies have demonstrated that anthracyclines induce cardiomyocyte myofibrillar disarray [17] and apoptosis [12]. While it is difficult to completely unify these diverse

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cytotoxic effects to one mechanism of cellular injury, many studies have suggested a central role of oxidative stress, leading to increased reactive oxygen species, lipid peroxidation, and iron-regulated oxidative damage. Such studies have provided the mechanistic basis for cardioprotective strategies (discussed below), which have had mixed results in the clinical setting. Over the past 2 decades data have emerged to suggest that alternative mechanisms independent of ROSmediated damage are important in anthracyclineinduced cardiotoxicity [1]. Such alternative mechanisms may be better targets for more effective cardioprotective strategies. One such alternative theory proposes that oxidative stress (mediated by the formation of ROS by redox cycling of anthracyclines) plays a primary role only in the development of acute anthracycline cardiotoxicity, while secondary alcohol metabolites of anthracyclines accumulate in cardiac tissue over time and lead to chronic cardiotoxicity [2]. Anthracycline molecules bear a quinone moiety that can be reduced by two electrons to form secondary alcohol metabolites such as doxorubicinol [18]. Such metabolites potently impair cardiomyocyte calcium handling to a much greater degree than their parent compounds through effects on calcium handling proteins [19] and on sarcoplasmic reticulum Ca2+-induced Ca2+ release [20] in a free-radical independent manner.

9.2.3 Synergistic Interactions Anticancer agents that are commonly co-administered with anthracyclines or commonly administered in patients previously treated with anthracyclines may enhance cardiac toxicity of anthracyclines, despite the fact that such agents alone exhibit minimal cardiac toxicity. One such class of drugs is the taxanes, which are microtubule-stabilizing drugs that inhibit tumor growth by causing cell-cycle arrest. Paclitaxel and docetaxel, both widely used taxanes, have both been shown to increase formation of doxorubicinol, the secondary alcohol metabolite of doxorubicin. Kinetic studies showed that at low doses (such as those given to patients), taxanes bind with high affinity to a regulatory or allosteric site of the aldehyde reductase enzymes

A.Y. Khakoo and C.S. Kwartler

that convert anthracyclines to their metabolites. However, at high doses taxanes begin to compete with anthracyclines to bind to the active sites of these enzymes and thus prevent alcohol formation [21]. Clinically, initial studies demonstrated an enhancement of anthracycline-induced cardiac toxicity occurring when co-administered with paclitaxel; [22] however, subsequent adjusted dosing regimens have minimized this effect [23]. The use of docetaxel simultaneously with doxorubicin does not appear to enhance the rates of clinically significant cardiac toxicity compared with anthracyclines administered as a single agent [23]. Co-administration of anthracyclines and the antiErbB2 antibody trastuzumab results in a high rate of heart failure. Up to 28% of patients treated with this regimen experienced a cardiac event [24, 25] with 15% experiencing a grade 3 or 4 complication [26]. One hypothesis to explain this synergistic relationship is that trastuzumab alters ErbB2 signaling to interfere with the regulation of cytoskeletal proteins, while anthracyclines directly affect biosynthesis of sarcomeric proteins. These two independent mechanisms both leading to an effective contractile dysfunction could be causing the additive effect of cardiotoxicity [27]. More frequently cited, however, is the “multiple hit” hypothesis: that anthracyclines induce oxidative stress, and myocytes typically signal through survival pathways like ErbB2 in response to that stress. In fact, data in anthracycline-treated patients suggest that ErbB2-dependent signaling in the myocardium may be particularly important in the setting of anthracycline treatment. Myocardial uptake of indium-labeled trastuzumab was seen in 50% of patients within 3 weeks after anthracycline treatment, while only 9% of patients exhibit myocardial uptake of labeled trastuzumab 11 months after anthracyline administration, and no uptake is detected in the hearts of patients with heart failure not due to anthracyclines [28]. It is essential to be wary of combining new drugs with anthracyclines, as these examples show. Another study on pharmacokinetics of doxorubicin showed that even drugs that do not react with the quinone moiety to increase ROS formation or with the reductase enzymes to speed secondary alcohol metabolite formation can still cause increased cardiotoxicity by competing

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sterically for anthracycline-degrading factors like MbIV-O. Even drugs with no cardiotoxic effects themselves could interfere with doxorubicin metabolism in this way [29].

9.2.4 Cardioprotective Strategies Since anthracycline-induced cardiotoxicity is irreversible and usually unresponsive to traditional heart failure treatments like digitalis, ACE inhibitors, and beta-blockers,

several strategies have been developed to reduce the risk of heart failure due to anthracyclines. Table 9.2 summarizes the results of several strategies to reduce the risk of cardiotoxicity resulting from anthracyclines. Continuous infusion of anthracycline as opposed to standard, bolus therapy showed initial promise as a cardioprotective strategy [30]. Enthusiasm for this approach was tempered by other reports that were unable to reproduce this cardioprotective effect [31]. Thus, there remains a wide spectrum of administration protocols for anthracycline infusion at different centers, with continuous infusion reserved for patients at high risk for cardiotoxicity.

Table 9.2  Cardioprotective strategies for anthracyclines Strategy

Doxil (Pegylated Lipoxomal Doxorubicin) [34, 35, 206, 207]

Slow infusion (>6 hours) [30, 31, 208]

Dexrazoxane[40]

ACE inhibitors [46, 209]

Beta blockers [45, 209]

Net decrease of Cardiotoxicity

RR= 0.38 for heart failure combined

RR = 0.27 for clinical heart failure, also protective against subclinical disease

RR = 0.29 for heart failure combined

Significant increase in average LVEF after treatment

Significant increase in avg LVEF after treatment

Effect on Cancer therapy efficacy

RR = 1.01 for tumor response, 1.01 for progression free survival

RR = 1.2 for tumor response, 1.42 for overall survival (difference  not statistically significant)

RR = 0.89 for tumor response, 1.01 for progression-free survival

None reported

None reported

Adverse effects

increased skin toxicity (PPE), bone marrow toxicity, and infusion reactionsp; decreased alopecia, myelosuppression, mucositis

Decreased gastrointestinal effects, no effect on myelosuppression or alopecia

No change in thrombocytopenia, neutropenia, slight increase in abnormal white blood cell count  and anemia (RR=1.19); increased pain on injection; increased phlebitis and fever; decreased stomatitis, nausea/vomiting; one studied suggested high risk of secondary malignant disease

Incraesed incidence of dizziness, hypotension, and fatigue Fetal kidney damage if taken during pregnancy

None specifically reported Beta-blockers can increase risk of hypoglycemic shock in diabetic patients, and can reduce circulation to extremitie, dizziness and clinical depression are also common

Other notes

Doxil formulation has greatly increased half-life and higher uptake in tumor cells

This strategy is used routinely at MD Anderson Cancer Center; some evidence suggests it is not effective in children

Dexrazoxane is the only co-drug that has been proven to be cardioprotective by several rigorous clinical trials

ACE is are also used to slow progression of cardiomyopathy once it occurs

Beta-blockers are also used to slow progression of cardiomyopathy once it occurs

RR risk ratio (<0.5 is significantly beneficial, >2 is significantly harmful)

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Changes in the chemical structure or method of formulation of anthracyclines have also been devised in an effort to reduce cardiotoxicity without reducing tumor efficacy. Epirubicin is a structurally modified analog of doxorubicin, which has less toxicity on an equimolar basis [32], but comparative studies have not detected a significant difference in cardiotoxicity between these two drugs when used at dosages that are efficacious in cancer therapy [33]. Pre-clinical studies strongly suggest that epirubicin is converted to its secondary alcohol metabolite epirubicnol at a much lower efficiency than conversion of doxorubicin to doxorubicinol [2]. Thus, one would predict that epirubicin would have significantly lower incidence of chronic cardiac toxicity compared with doxorubicin when used at dosages with equivalent anticancer efficacy, but this has not yet been clearly demonstrated in head-to-head clinical trials. Furthermore, a meta-analysis of five randomized, controlled trials found no significant difference between rates of cardiotoxicity associated with epirubicin compared with that of doxorubicin [34]. More favorable findings have been demonstrated with the use of liposomal anthracycline formulations, particularly with pegylated liposomal doxorubicin (PLD, Doxil) [35, 36]. In a large phase III trial of patients with metastatic breast cancer that compared conventional doxorubicin and PLD, the latter was associated with a highly significant (P < 0.0001), threefold decreased risk in cardiotoxicity, with no difference in antitumor efficacy [35, 36]. The EDTA-like iron chelator dexrazoxane has also shown promise in preventing anthracycline-induced cardiotoxicity. Dexrazoxane was originally itself an anticancer drug whose cardioprotective effects were discovered accidentally [3]. Treatment of cultured cardiomyocytes with doxorubicin causes loss of mitochondrial DNA and cell death, pre- or co-treatment with dexrazoxane significantly reduces these effects [37]. Dexrazoxane has two mechanisms of action: in tumor cells it, like anthracyclines, is a strong inhibitor of topoisomerase II. In cardiomyocytes, meanwhile, it is metabolized to an EDTA-type form that chelates iron and prevents oxidative damage to the cells [38]. In one of the first randomized trials of this agent, patients treated with dexrazoxane had significant decreases in the incidence of cardiotoxicity caused by doxorubicin as determined by the development of congestive heart failure (CHF) left ventricular dysfunction (LVD) and changes on endomyocardial biopsy

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consistent with anthracycline cardiotoxicity [39]. A meta-analysis of six randomized, controlled trials concluded that ­dexrazoxane significantly reduces the incidence of anthracycline-induced heart failure [relative risk (RR) = 0.28, CI 0.18–0.42, P < 0.000001] [40]. This same meta-analysis identified a trend towards decreased tumor response in patients receiving dexrazoxane (RR = 0.88, CI 0.77–1.01, P = 0.06), although a significant worsening in tumor response rate in patients treated with dexrzoxane has only been observed in one study [41]. Notably, although dexrazoxane can worsen both thrombocytopenia and granulocytopenia during cancer therapy, no significant difference in the incidence of these adverse effects was identified in the meta-analysis. Furthermore, an overall survival benefit has not been observed in patients receiving dexrazoxane for cardioprotection in either a large randomized trial [41] or in the meta-analysis of six randomized studies [40]. For all of these reasons, the usage of dexrazoxane is limited to subsets of pediatric patients and patients at high-risk of cardiotoxicity due to anthracyclines, such as those with pre-existing cardiac disease. The nonspecific beta-blocker carvedilol, a mainstay of therapy for patients with heart failure, has potent antioxidant and antiapoptotic properties, which suggest that it may be effective as a protective agent for anthracycline-induced cardiotoxicity [42]. Preclinical studies have demonstrated that carvedilol protects cardiomyocytes from anthracycline-induced damage in vitro [43] and in animal model studies [44]. A recent small, placebo-controlled study demonstrated a similar cardioprotective effect of once-daily carvedilol in patients receiving anthracycline-based chemotherapy [45]. Larger, randomized clinical studies are needed to confirm the utility of carvedilol as a cardioprotective agent for patients receiving anthracycline-based chemotherapy. A recent report integrating the use of cardiac biomarkers with the use of the angiotensin-converting enzyme (ACE) inhibitors as a chemoprotective strategy demonstrated a promising approach [46]. In a randomized study of patients who received high-dose chemotherapy with elevated serum troponin I levels, none of the 56 patients randomized to receive enalapril developed heart failure, while 14 of 58 (24%) control patients developed heart failure. This finding was consistent with pre-clinical observations demonstrating that ACEinhibitors provide a powerful cardioprotective effect in animals receiving anthracyclines [47, 48]. While we

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await further large trials of these chemoprotection strategies, it is reasonable to use ACE-inhibitors prophylactically in patients receiving anthracyclines who have a high-risk of developing cardiotoxicity or in whom antihypertensive therapy is indicated. This approach is in accordance with the recently updated American Heart Association/American College of Cardiology guidelines for the treatment of heart failure [49]. Many other molecules and drugs have been tested as potential cardioprotective agents, with several showing promise in cell culture or animal studies. For example, probucol is an antioxidant with lipid-lowering effects, and has been shown to effect doxorubicin pharmacokinetics without affecting antitumor efficacy. Pretreatment with probucol significantly decreases doxorubicin concentrations in plasma and also reduces markers of cardiac damage in pre-clinical studies [12, 50]. Two hypotheses about its mechanism have been proposed: either probucol could inhibit conversion of doxorubicin into its toxic secondary alcohol metabolite doxorubicinol or its effect may be to accelerate excretion of the drug through the kidney through an antioxidant effect, thus reducing dosage to the heart. Modulation of diet and exercise has also been shown to be potentially cardioprotective. In mice, increased exercise training has been shown to be protective particularly against acute anthracycline cardiotoxicity and may also protect against chronic effects [51]. Meanwhile, rats fed with a high-fat diet show an increased sensitivity to doxorubicin that may be due to preexisting cardiac stress [52], suggesting that restricting diet or increasing exercise to improve overall cardiac health may reduce cardiotoxicity caused by anthracyclines.

9.2.5 Conclusions Although recent studies have significantly advanced our understanding of anthracycline-induced cardiotoxicity, many questions still remain. The search for human genetic variants, the use of cell culture and animal models to probe specific mechanisms, and the preclinical and clinical studies of treatments that may be cardioprotective or sensitizing have so far yielded strong results that are just beginning to make sense together. Since the cardiac damage caused by anthracyclines is irreversible, clinically relevant, and potentially fatal, the urgency of this research is not

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diminishing. Reducing the incidence of anthracycline cardiotoxicity through better drug development, cardioprotective strategies, and modulation of treatment based on genetic risk will improve outlook for many cancer survivors.

9.3 Mitoxantrone Mitoxantrone is a broad-spectrum anticancer drug with a similar structure to anthracyclines called an anthraquinone. It is a DNA intercalating agent and a ­topoisomerase II inhibitor with similar antitumor mechanisms to anthracyclines [53]. Phase I and II trials for mitoxantrone revealed incidents of cardiac failure and arrhythmias, including a 13% rate of LVEF decline and a 2.6% rate of heart failure. These ­reactions appeared to be dose dependent [54]. Mitoxantrone-induced cardiotoxicity, like anthracycline cardiotoxicity, can manifest as either an acute or chronic type [55]. An early randomized clinical trial comparing mitoxantrone to doxorubicin showed that although cardiac function declined on both drugs, treatment with doxorubicin caused a more accelerated drop. Risk of leaving the study due to cardiac events and risk of developing full-blown congestive heart failure were both also higher in doxorubicin-treated than mitoxantrone-treated patients [56]. A more recent trial again comparing mitoxantrone to anthracyclines in Hodgkin’s disease patients had the reverse result, demonstrating a significantly increased incidence of clinically relevant cardiac events and cardiac mortality on mitoxantrone compared with doxorubicin or epirubicin [57].

9.3.1 Mechanistic Insights Mitoxantrone causes similar ultrastructural pathology in the heart to that seen with anthracyclines: features of my­ofibrillar loss, sarcotubular dilation, and mitochondrial swelling [58]. These similarities suggest similar mechanisms to induce cardiac damage. Indeed, as discussed above, doxorubicin induces mitochondrial-mediated apoptosis pathways in cardiomyocytes. Similar apoptotic induction was observed with mitoxantrone [53]. Mitoxantrone has been shown to be a potent blocker of certain potassium channels, which causes a

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prolongation of the action potential in cardiomyocytes and may predispose to arrhythmias [58]. A comparison of cellular effects of doxorubicin vs. mitoxantrone showed that both drugs also delay calcium uptake by the sarcoplasmic reticulum (SR), but while doxorubicin also inhibits SR calcium release, mitoxantrone enhances SR calcium release [59]. Further studies need to be done to continue to clarify in what ways mitoxantrone cardiotoxicity is similar to and different from anthracycline cardiotoxicity, and to determine whether similar cardioprotective methods could be applied to mitoxantrone.

9.4 Tyrosine Kinase Inhibitors Tyrosine kinase inhibitors (TKIs) are targeted therapies in the form of either monoclonal antibodies or small molecule inhibitors that restrict cell signaling through kinases known to be important in cancer, for example, the ErbB2 receptor in breast cancer. Conceptually, by specifically inhibiting tyrosine kinases overexpressed in tumor cells, these therapies will be more effective against cancer cells and cause less damage to normal organs [60]. While these therapies are very effective for the treatment of cancer, some of them turned out to cause cardiotoxic effects. For multitargeted kinase inhibitors especially it is important to determine which pathways are causing the cardiac effects so better TKIs can be developed without those “off-target” effects [61].

9.4.1 Trastuzumab Trastuzumab is a monoclonal antibody against the ErbB2 receptor (also known as HER-2) approved for the treatment of ErbB2 positive breast cancer in 1998. ErbB2 is a member of the epidermal growth factor receptor family which includes EGFR and ErbB2-4. Approximately 1/3 of all breast cancers show a 10- to 100-fold increase in ErbB2 expression, and this phenotype is associated with poor prognosis [30]. Treatment with trastuzumab has significantly improved overall survival and disease-free survival rates in women with breast cancer [62]. Several studies have reported left ventricular dysfunction in up to 10% of patients and

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development of congestive heart failure in 1–4% of patients treated with trastuzumab alone [63–65]. Cumulative dose of the drug does not appear to be related to cardiac complications, and the effects are mostly reversible upon discontinuation of treatment [66]. No ultrastructural changes are observed in the myocardium of these patients, including no vacuolization or myocyte loss [64]. Risk factors for trastuzumab-induced cardiac dysfunction include older age, preexisting cardiovascular disease including coronary artery disease, diabetes, and valvular disease, and possibly prior radiation therapy to the left breast. Trastuzumab also causes synergistically increased toxicity when combined with anthracyclines (see anthracyclines section) or paclitaxel: up to 28% of women treated with anthracyclines and trastuzumab and 13% of women treated with paclitaxel and trastuzumab developed significant cardiac dysfunction [25, 67]. Paclitaxel, a taxane drug, causes a decrease in ERK1/2 phosphorylation, which leads to an increase in myofilament degradation; similar effects are seen with ErbB2 inhibitors. The combination of these two drugs increases diastolic calcium, shortens relaxation time, and reduces fractional shortening in heart tissue, suggesting an additive effect of cardiac dysfunction [68]. The question remains why cardiac tissue is sensitive to trastuzumab in spite of a relatively low level of ErbB2 receptor expression. ErbB2 was known to be required for formation of the heart, as knockout mice cause embryonic lethality due to defects in cardiac development. However, the role of ErbB2 signaling in the adult heart was unknown, until clinical cardiotoxicity associated with trastuzumab prompted a closer look. Conditional, cardiac-specific ErbB2 knockout mice have a dilated cardiomyopathy phenotype and exhibit excess mortality in response to pressure overload stress [69]. Trastuzumab has been shown to effectively phosphorylate ErbB2 in the human heart, and treatment over the course of weeks has been shown to induce breakdown of myocardial fibers and loss of the beating contractions [27]. Two hypotheses have been suggested. First, ErbB2 may be nonrandomly localized on the cell surface in such a way that it is easily targeted by trastuzumab. There is evidence that ErbB2 heterodimerizes with ErbB4 to signal in the heart and that both proteins localize specifically to the T-tubule. Alternatively, minor perturbations in ErbB2 signaling may be

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particularly devastating to cardiomyocytes. In chimeras where a subset of cells was ErbB2 negative, the entire heart was still unable to contract properly [27]. Another question is why only a small subset of patients develops cardiac dysfunction on trastuzumab if the ErbB2 pathway is so critical for cardiomyocyte function and survival. One hypothesis is that multiple “hits” are required: a heart with preexisting or concurrent stress, caused by prior heart disease or anthracycline treatment, would need to signal through ErbB2 more in order to maintain function [63]. Patients with these risk factors do show increased sensitivity to trastuzumab, supporting this theory. Another theory is that natural variability in expression of neuregulin genes NRG1 and NRG2 in the heart leaves some patients more vulnerable to trastuzumab-induced cardiac damage. One study showed that only a subset of patients absorbs the drug into the myocardium, and all of these patients developed cardiotoxicity [27, 70]. It is unknown what makes these patients more susceptible, but higher levels of ErbB2 expression or lower levels of ErbB4 expression (effectively mimicking higher levels of ErbB2) could also contribute to sensitivity. Despite a significant incidence of CHF as a result of trastuzumab treatment, cardiotoxicity caused by trastuzumab results in substantially lower morbidity and mortality compared with CHF due to anthracyclines [71]. The reversibility of cardiac dysfunction caused by trastuzumab was suggested by a study of 38 anthracycline-treated breast cancer patients who subsequently developed cardiac dysfunction (mean pre-treatment ejection fraction 61%; mean post-trastuzumab ejection fraction 45%) [64]. After discontinuation of trastuzumab and aggressive treatment with ACE inhibitors and beta blockers (BB), cardiac function returned to near-baseline levels in nearly all of these patients. Moreover, 25 of these patients were maintained on standard heart-failure therapy and were successfully rechallenged with trastuzumab without a subsequent decline in cardiac function.

9.4.2 Lapatinib Lapatinib is also an ErbB2 inhibitor, but is a small molecule rather than a monoclonal antibody targeting the EGF-receptor [61]. In a study of 3,700 patients, 60

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(2%) experienced cardiac events. No risk factors were identified, and cumulative dose was not related to incidence of cardiotoxicity. Cardiac events, including cardiac failure and palpitations, were generally reversible [72]. An analysis of multiple trials of patients treated with lapatinib for a variety of solid tumors showed that 1.6% of patients had a decline in the left ventricular ejection fraction, while 0.2% developed symptomatic congestive heart failure. The difference in cardiotoxicity between trastuzumab and lapatinib has not yet been explained. One possibility is that since trastuzumab is a monoclonal antibody, it may have immune-mediated effects on cardiomyocytes that are not replicated by the small molecule inhibitor lapatinib. Another explanation could be that these two drugs, despite targeting the same receptor, may trigger different intracellular signaling responses in cardiomyocytes, but not in cancer cells. A detailed molecular understanding of the differences between trastuzumab and lapatinib on cardiac function may provide key insights into the role of ErbB2 in cardiac function and may also provide insights into novel strategies for cardioprotection. A third possibility is that there is not a great inherent difference in cardiotoxicity, but that because of the findings with trastuzumab, patients were more carefully selected for lapatinib trials. For example, after the discovery of a severe increase in toxicity when trastuzumab and anthracyclines are used concurrently, patients receiving anthracycline treatment were screened more heavily for lapatinib trials [66].

9.4.3 Imatinib Imatinib was designed to inhibit Abl kinase, but also targets PDGF-receptors, c-Kit, and other pathways. It is used in the treatment of hematological malignancies and gastrointestinal stromal tumor (GIST). More than 80% of chronic myelogenous leukemia patients achieve full remission with imatinib treatment. Initial clinical trials, which likely excluded patients at high risk for cardiovascular disease, found no evidence of cardiotoxicity caused by imatinib. In 2006, however, a study was published on ten individuals who developed severe congestive heart failure during imatinib therapy. The pathology of these patients’ myocardiums revealed membrane whorls, pleomorphic mitochondria, and

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glycogen accumulation [73]. The same study reported that mice treated with imatinib developed cardiac dysfunction associated with activation of the ER stress response and resulting in histological findings similar to those observed in patients. The toxic effects of imatinib on cardiomyocytes were linked to inhibition of Abl kinase. Consistent with these findings, a modified form of imatinib, which has a specific reduction in activity against Abl kinase, produces substantially less cardiac toxicity in a murine model [74]. Despite these compelling findings, the incidence of clinically significant cardiomyopathy and heart failure attributable to imatinib appears to be low. A retrospective study of patients with CML treated with imatinib found that 1.7% of patients develop heart failure [75]. Risk factors included older age, prior treatment with anthracyclines or interferon, and prior history of cardiac disease or risk factors, but did not include increased dose of imatinib. Similarly, a retrospective study of gastrointestinal stromal tumor patients reported an incidence of heart failure and cardiomyopathy attributable to imatinib of less than 1% [76]. It is important to note that retrospective studies can underestimate the incidence of cardiotoxicity, particularly overlooking subclinical decreases in cardiac function. Nevertheless, based upon the existing data, the clinical significance of cardiotoxicity due to imatinib seems to be small. However, in light of preclinical findings suggesting that imatinib impairs aspects of the cardiac stress response, the long-term consequences of imatinib therapy warrant further, prospective study, particularly in patients with preexisting cardiovascular disease and when combined in anticancer regimens containing other established cardiotoxins.

9.4.4 Dasatinib and Nilotinib Dasatinib and nilotinib are both Abl kinase inhibitors developed for use in imatinib-resistant or -intolerant patients with leukemias [77, 78]. Dasatinib also inhibits Src family kinases, c-Kit, PDGF-receptors, and ephrin-A. In vitro studies suggested both drugs could potentially cause prolonged QT interval. Only 1% of patients treated with dasatinib, however, developed significant QT prolongation [78], whereas 3% of nilotinib treated patients develop significant QT

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prolongation [79]. QT prolongation should be ­managed by discontinuation of the drug or dose reduction. A clinically significant incidence of cardiomyopathy or heart failure associated with nilotinib or dasatinib has not been reported. Up to 35% of CML patients treated with dasatinib develop pleural effusions [80], with a significant number of such patients also developing pericardial effusions. However, these adverse effects do not appear to be the result of cardiac dysfunction. The etiology of such effusions appears to be multifactorial, due in part to generalized fluid retention, and possibly also attributable to immune-mediated effects [81]. Nilotinib is also associated with both pleural and pericardial effusions, albeit at a much lower frequency [77].

9.4.5 Sunitinib Sunitinib is an extremely promiscuous multiple tyrosine kinase inhibitor. In one study, sunitinib reacted with 18% of all kinases tested, a percentage that suggests the possibility of an extremely high number of kinases inhibited in  vivo [82]. Sunitinib activity against both VEGFR and PDGFR make it a highly antiangiogenic agent, which is the dominant mechanism of its antitumor effect. Sunitinib is approved for treatment of metastatic renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors. Questions about the cardiac safety of sunitinib emerged from early clinical trials of the drug. In one study of patients with GIST, 10% of patients experienced left ventricular dysfunction compared with 3% treated with placebo [83]. Similarly, in one study, patients with metastatic renal cell carcinoma treated with sunitinib developed LVD 15% of the time [84]. In a study of 75 sunitinib-treated patients with no prior history of cardiac dysfunction, 19% of patients experienced a 15% or greater decline in ejection fraction, whereas 8% of patients developed cardiac dysfunction along with advanced heart failure symptoms [85]. Forty-seven percent of these patients experienced hyper­tension, including 17% with grade 3 or greater hypertension. In another study of metastatic renal cell carcinoma patients, 19% had substantial declines in left ventricular function with 7% experiencing left ventricular dysfunction and advanced heart failure. All of the heart failure patients also had grade

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3 hypertension [86]. In a referral-based study, six sunitinib-treated patients (3%) with no history of heart disease developed severe left ventricular dysfunction and heart failure associated with marked cardiac morbidity or mortality [87]. In each of these studies, the onset of cardiac toxicity from initiation of therapy was less than 6 months and was associated with the development of profound hypertension. Risk factors for development of sunitinib cardiotoxicity included history of hypertension and history of coronary artery disease. Studies reporting a higher incidence of hypertension also reported a higher percentage of patients developing heart failure [86]. Cardiotoxicity does not appear to be dose-dependent, and cardiac damage appears to be incompletely reversible after discontinuation of treatment [88]. Endomyocardial biopsies from patients with sunitinib cardiotoxicity showed hypertrophy and swollen mitochondria with membrane whorls. No inflammation or fibrosis was seen [85]. In the patients examined, there were no signs of ischemia or valvular damage, but histology showed loss of cellular mass with fragmented myocardial muscle bundles [89]. Few mechanistic studies have been done, but it appears hypertension may precede or contribute to sunitinib toxicity. Inhibition of PDGF-receptor signaling has been suggested as a possible mechanism for sunitinib cardiotoxicity. PDGF-receptor signaling stimulates myocyte growth in response to hypertensive stress [87]. However, endogenous PDGF signaling has not been shown to be cardioprotective, though overexpression of PDGF has [61]. A combination of hypertension and inhibition of key tyrosine kinases may be the cause of cardiotoxicity.

9.4.6 Sorafenib Sorafenib is also a multi-kinase inhibitor used in the treatment of renal cell and hepatocellular carcinoma, and is in trials for treatment of metastatic melanoma and non-small-cell lung cancer. Its targets include Raf-1, b-Raf, PDGF-receptor, VEGF-receptor, c-Kit, and Flt3 [90]. As Raf kinases and VEGF-receptor signaling are important in angiogenesis, sorafenib can be considered an antiangiogenic drug. A common side effect of all antiangiogenic drugs, including sorafenib, is hypertension [91]. Treatment with

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sorafenib reduces proliferation of vascular smooth muscle cells and increases apoptosis of these cells [90]. Its hypertensive effect is likely mediated thro­ ugh effects on vascular rarefaction and nitric oxide ­production associated with vascular endothelial dysfunction. Sorafenib also induces acute coronary symptoms, including myocardial infarction, in 2.9% of patients [92]. Some patients developed severe cardiac effects without prior history of heart disease or hypertension [93]. It may also cause a higher incidence of less dramatic cardiac events. Reinitiation of therapy after treatment of cardiovascular complications did not cause further problems [94]. In patients with poorly controlled hypertension, pressure load on the heart increases, and the normal response is to increase angiogenesis in the heart. Inhibition of angiogenesis by sorafenib may lead to heart failure in these patients [61, 95]. Sorafenib is significantly more toxic to cells relying entirely on mitochondria for energy generation. The drug has been shown to inhibit all complexes (I–V) in the mitochondrial electron transport chain. These experiments suggest that damages to mitochondrial energy metabolism processes might be a key cardiotoxic effect of sorafenib [92].

9.4.7 Bevacizumab Bevacizumab is a monoclonal anti-VEGF antibody approved to treat metastatic colon cancer, renal cell cancer, breast cancer, kidney cancer, and non-smallcell lung cancer. It is an angiogenesis inhibitor that also affects tumor vasculature in a way that improves delivery of other chemotherapeutic drugs and decreases pressure inside tumors. Like other angiogenesis inhibitors, it causes a significant percentage of patients to develop hypertension [96, 97]. Grade 3 or 4 hypertension is seen in 8–18% of patients, and the incidence appears to be dose-dependent. Risk of hypertension also increases with age over 75, African-American race, and specifically renal cell cancers [96]. This drug also causes an increase in severe cardiovascular complications. One study reported 2.1% of patients had myocardial infarctions, 2.5% had cerebrovascular accidents, 1.8% had hemorrhagic bleed in the gastrointestinal tract, 2.0% developed congestive heart

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failure, 3.0% developed angina, and 1.8% died suddenly over a 1 1/2-year period of bevacizumab treatment. Prior history of cardiovascular disease was a significant risk factor, and anthracycline treatment or radiation to the heart may also increase risk [98]. Many of these cardiovascular events were probably related to an increase in risk of arterial thromboembolism with bevacizumab treatment [5]. Age over 65 and prior history of thromboembolism are risk factors, but cumulative dose is not. Therapy with bevacizumab should be permanently discontinued in case of this type of complication. Thromboembolic effects may be mediated by a persistent inflammatory state that results from VEGF inhibition [96]. Mice with an endothelial-specific deletion of VEGF experience progressive endothelial degeneration leading to thrombosis [95]. The complication of hypertension is most likely due to inhibition of nitrous oxide synthase, causing vasoconstriction and a decrease in sodium ion excretion. These effects both raise blood pressure. Decreased capillary density, increased vascular resistance, disrupted balance of endothelin, and vascular rarefaction may also contribute to the hypertensive phenotype. Although most adult blood vessels were previously thought not to require VEGF signaling for maintenance, many recent studies refute that claim. Capillaries with endothelial fenestrations are most dependent on VEGF signaling and regress with VEGF inhibition [99]. This finding may help identify tumors most likely to respond to this therapy. Treatment with anticoagulants, ACE inhibitors, and calcium channel blockers may help to prevent the vascular side effects of bevacizumab.

9.4.8 Conclusions Contrary to the initial goals of targeted molecular therapeutics, it appears that tyrosine kinase inhibitors are frequently associated with a small but clinically important risk of severe cardiovascular complications. Prospective studies of cardiac function are needed for all of these drugs to determine the true incidence of hypertension, arrhythmias, cardiac ischemia, and congestive heart failure. Retrospective studies based on adverse event reports are likely to underestimate risks.

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As more targeted therapies are designed, researchers and clinicians should be aware of potential cardiotoxic effects. Many kinases have a known role in the heart, and as drugs are designed against them we should be especially careful. For example, loss of Jak1, Jak2, or Stat3 in the heart increases sensitivity to cardiac damage including that caused by anthracyclines. The drug lestaurtinib inhibits Jak2, and patients should be monitored for cardiac function during clinical tests of this drug. Another example is the drug perifosine, an inhibitor of Akt kinase, which has recently been identified as important for normal cardiac growth and response to stress. Vigilant monitoring for cardiotoxicity in patients treated with this agent may also be warranted.

9.5 Monoclonal Antibody Therapies 9.5.1 Alemtuzumab Alemtuzumab is a monoclonal antibody against CD52 and is used to treat chronic myelogenous leukemia. Initial infusion-related toxicity symptoms can include dyspnea and hypotension, but with a gradual increase of dose this reaction can be avoided [100]. Mycosis fungoides and Sezary syndrome are also sometimes treated with alemtuzumab, and one small study of this patient population reported an unacceptably high incidence of cardiac effects, including congestive heart failure, arrhythmias, deep venous thrombosis, severe hypotension, and vascular leak syndrome [101]. However, a subsequent retrospective analysis by another group identified no clinically significant cardiotoxicity in mycosis fungoides/Sezary syndrome patients treated with alemtuzumab [102]. CD52 is not expressed in cardiomyocytes or endothelial cells, so direct cardiovascular toxicity is unlikely, but rare incidences of cardiac effects may be mediated by inflammatory cytokine release leading to coronary spasm.

9.5.2 Rituximab Rituximab is a chimeric monoclonal antibody against CD20 used to treat multiple malignant and benign hematological conditions. Rituximab can cause severe

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infusion reactions that include hypotension and angioedema, with very severe reactions occurring in 1% of patients [103]. Rituximab is generally well tolerated with minimal cardiovascular toxicities, such as angina, which has been reported in less than 1% of infusions.

9.5.3 Cetuximab Cetuximab is a monoclonal anti-EGF-receptor antibody used to treat metastatic colon cancer either as a single agent or with irinotecan. It can cause a severe infusion reaction with hypotension in up to 3% of patients. This reaction can sometimes be fatal [103].

9.6 5-Fluorouracil and Capecitabine 5-Fluorouracil (5-FU) is an antimetabolite used to treat solid tumors of the breast, head, neck, and GI tract [95]. It inhibits thymidylate synthase in cancer cells and ultimately causes cell death [104], 5-FU is well known to cause myocardial ischemia and rarely myocardial infarction. The incidence of 5-FU cardiotoxicity has been reported in the range of 1.2–18%, depending on the treatment regimen and co-drugs. In a prospective analysis of patients receiving high-dose 5-fluoruracil by continuous infusion (600–1,000 mg/ m2/day), 7.6% experienced cardiac events during infusion [105]. Although the symptoms were transient in most of these patients, 2.2% of patients experienced cardiac death due to arrhythmias or circulatory collapse. More recently, a series of 427 patients receiving high-dose, continuous infusion 5-fluorouracil identified symptomatic cardiac toxicity with ischemic EKG changes in 17 treated patients (4%) during drug infusion [106]. Clinical improvement was noted in most patients with termination of infusion and administration of nitrates, but one patient died of an arrhythmia. Patients with established coronary artery disease may be at higher risk of developing myocardial ischemia during infusion of 5-FU [107]. Chest pain and EKG changes suggestive of myocardial ischemia have also been described in patients treated with capecitabine, an orally administered prodrug of 5-fluorouracil [108]. The nature and

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extent of capecitabine-induced myocardial ischemia may be similar to that of infusional 5-fluorouracil, although larger studies are needed to evaluate the risk of myocardial ischemia and infarction attributable to these two agents. Coronary vasospasm is an important mechanism leading to myocardial ischemia and/or infarction associated with 5-FU. In vitro experiments show that therapeutic levels of 5-FU cause a vasoconstriction effect in smooth muscle, possibly mediated by effects on protein kinase C and reversible by nitrate therapy [109]. Clinical research confirms that patients have a significantly decreased brachial artery diameter upon treatment with 5-FU. In addition, some reports suggest 5-FU can also cause non-ischemic cardiomyopathy and myocarditis [104], although this does not appear to occur commonly in clinical practice at usual dosage regimens.

9.7 Cyclophosphamide Cyclophosphamide is used in combination chemotherapy for several solid tumors and lymphomas, and is used at high dosages as a conditioning regimen prior to bone marrow transplantation. Although cyclophosphamide is well tolerated at lower dosages, LV dysfunction and CHF have been reported with high-dose regimens [110]. The myocardial injury due to highdose cyclophosphamide may be largely reversible [111], but significant morbidity and mortality have been seen in patients with cyclophosphamide-induced cardiac dysfunction [111]. Similarly, Quezado et  al. [112] have also reported a significant, dose-related incidence of CHF and arrhythmias in patients given ifosfamide. As with cyclophsphamide, ifosfamideinduced cardiac dysfunction appears to be transient and reversible. Pericarditis is another established cardiovascular toxicity associated with cyclophosphamide therapy [113]. The risk of cardiovascular toxicity due to cyclophosphamide increases with greater one-time doses of cyclophosphamide, but does not increase with cumulative dose [114]. Prior anthracycline treatment, prior irradiation to the heart, and a history of cardiovascular disease appear to increase the risk of cyclophosphamide cardiotoxicity [113–115].

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9.8 Cisplatin and Cisplatin-Based Combination Therapies

9.8.1 Toxicity with Combination Therapies

Cisplatin is an alkylating chemotherapy agent that produces interstrand DNA cross-links. Early case reports suggested that vascular ischemic events could be associated with cisplatin-based therapy: myocardial infarction, cerebrovascular accident, and hypertensive events were reported in young patients with no risk factors for cardiovascular disease [116–118]. A retrospective analysis of urothelial transitional cell carcinoma patients revealed vascular events in 12.9% of patients receiving cisplatin, including deep venous thrombosis (DVT), pulmonary embolisms, arterial thromboses, cerebrovascular accidents, and angina pectoris. Risk factors for these events included history of peripheral vascular disease or coronary artery disease and a large tumor size in the pelvis [119]. While older studies report a low rate of thrombosis, more recent studies show a significantly heightened risk on cisplatin-based therapies, including a particularly dangerous risk of grade 4 or 5 thrombotic events [120]. Treatment with prophylactic anticoagulation or calcium channel blockers may allow patients to continue use of cisplatin [116, 119], which is a very effective drug for the treatment of solid tumors. Although the exact mechanism of cisplatin-induced vascular toxicity is unknown, some indications and theories have been reported. Alterations to the clotting cascade affecting coagulability have been suggested as a possible mechanism particularly for thrombotic-type events [120]. Hypomagnesemia is reported to occur in 77–87% of patients after cisplatin-based chemotherapy, likely because cisplatin induces a tubular injury in the kidney that decreases the rate of reabsorption of magnesium. Lower Mg2+ concentration increases Ca2+ influx and results in constriction of the blood vessels. Elevation of plasma levels of von Willebrand factor (vWF) may also contribute to development of vascular disease. Cisplatin is known to stimulate endothelial cells to secrete increased levels of vWF [118]. This mechanism may be more frequently responsible for cerebrovascular accident or thrombosis, particularly in elderly patients, as these events typically occur earlier in the treatment course, while hypomagnesemia may contribute more to development of later events, which are predominantly myocardial infarctions without endovascular disease.

There are two commonly used cisplatin-based chemotherapy regimens for the treatment of cancers, in particular testicular seminoma and germ cell tumors: PVB (cisplatin, vinblastine, and bleomycin) and BEP (bleomycin, etoposide, cisplatin). Cisplatin-based combination chemotherapies have shown a “cure rate” for testicular cancer of over 80%. Both treatment courses have been associated with vascular toxicities, including development of Reynaud’s phenomenon in 37% of patients on either regimen [121]. Risk factors for Reynaud’s phenomenon include a cumulative dose of bleomycin, PVB treatment rather than BEP treatment, and hypertension [122]. Age, tumor histology, and other toxicities were not predictive factors [123]. Several other vascular events were seen more rarely: myocardial infarction [122, 124], angina pectoris [125, 126], cerebrovascular events [121], heart failure [126], major thromboembolic events (DVT, pulmonary embolisms (PE)) [127], and transient ischemia of the toes [125]. Digital ischemia occurred in 21% of patients treated without cisplatin compared with 41% treated with cisplatin [123]. Bleomycin is thought to be the most important drug in the pathogenesis of Reynaud’s phenomenon, while cisplatin is the most likely cause of the other vascular toxicities.

9.9 Other Chemotherapeutic Agents 9.9.1 Bleomycin Bleomycin is a glycoprotein used in the treatment of lymphomas, germ cell testicular cancer, and squamous cell cancers. In addition to peripheral vascular toxicities that have been reported with combination cisplatin/blemyocin treatment (described above), bleomycin has been associated with a 2.8% incidence of severe chest pain of unclear etiology [128]. It also has been associated with the development of acute pericarditis in a small subset of patients [128, 129]. In rare cases with young patients there have been reports of myocardial infarction or myocardial ischemia associated with bleomycin treatment [130].

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9.9.2 Irinotecan Used in the treatment of gastric and colorectal cancer, irinotecan may be associated with increased incidence of venous and arterial thromboembolic events. Eleven of 50 patients over two clinical trials developed drugrelated thromboembolism when treated with irinotecan or irinotecan plus bevacizumab (no difference in incidence between the two treatment groups) [131]. These findings have not been reported subsequently by other groups.

9.9.3 Cytarabine Cytarabine, also known as cytosine arabinoside, is a pyrimidine agonist used to treat acute myeloid leukemia [54]. Pericarditis is a rare side effect of this drug, mostly published in case reports [132, 133]. Cardiac tamponade has been reported to occur in conjunction with pericarditis in some patients [134], and capillary leak syndrome with pulmonary edema and pericardial effusion has also been reported [135]. Most published cases of pericarditis also report simultaneous pulmonary failure [135]. In all cases of pericardial disease appear to be directly related to the toxicity of cytarabine. Corticosteroid treatment may be an appropriate therapy for pericardial damage in these patients [132, 133].

9.9.4 Gemcitabine Gemcitabine is an antimetabolic drug, related to cytarabine, used in the treatment of solid tumors (most frequently breast and GI cancers). Original phase I trials of the drug used as a daily infusion caused severe hypertension, but the currently approved treatment regimen eliminates that side effect [136]. There have been case reports of gemcitabine-caused myocardial infarction [137, 138] and atrial fibrillation [136, 139]. The time frame to development of arrhythmic complications is within 12-24  h after infusion [140]. Gemcitabine has been reported to cause ventricular tachyarrhythmias of grade 1–4 in 2.3% of patients, cardiac dysfunction (with decline in LVEF) in 1.8% of

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patients, and mild pericarditis in 0.2% of patients [136]. It has also been reportedly associated with cases of thromboembolism [140]. The pathophysiology of these toxicities is unknown.

9.10 Microtubule-Altering Therapies 9.10.1 Vinca Alkaloids The vinca alkaloids are a class of microtubule-targeting drugs used to treat a wide array of solid and hematological cancers. Their mechanism of action is to disrupt microtubule assembly and arrest cells at metaphase [141]. There have been reports of hypertension, myocardial ischemia, myocardial infarction, and other vaso-occlusive disease with these compounds [54]. Vinorelbine is used to treat non-small-cell lung cancer, ovarian cancer, and breast cancer [142–144], and has been reported to cause an acute ischemic event or infarction during or very shortly after treatment [144]. A meta-analysis suggested an incidence of cardio­ toxicity of 1% with vinorelbine [145]. Vinblastine, vincristine, and vindesine are three other vinca alkaloids shown to cause repolarization disorders, precordial pain, acute ischemia, or infarction [144]. Risk factors for vinca alkaloid toxicity include female gender [145], prior cardiac history [145], prior irradiation [144], and prior anthracycline therapy [144]. Several mechanisms have been proposed, including direct toxicity to myofibrils [143], coronary vasospasm [142], progressive dissolution of the sarcoplasm and formation of membranous bodies [146], an affect on coagulation leading to arterial occlusion [144], and disorganization of cellular microtubules leading to impairment of metabolism and impairment of contractility [144]. Interestingly, several reports of vincristine interactions with doxorubicin have been published, some suggesting a higher incidence of ischemic toxicity [147], and others suggesting vincristine is cardioprotective against doxorubicin effects [141, 148]. Cell culture studies show vincristine increases myocyte survival signaling [141] and decreases oxidative stress and apoptosis [148]. More studies are needed to confirm and further probe these effects.

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9.10.2 Taxanes Taxanes work by stabilizing microtubules and preventing depolymerization [149], and are used to treat breast, ovarian, and non-small-cell lung cancers [5]. As described above, pre-clinical studies have suggested that combination taxane/anthracycline therapy may enhance formation of cardiotoxic anthracycline metabolites, potentially offering an explanation of excess cardiac toxicity observed when doxorubicin and paclitaxel were co-administered in bolus-dosing regimens to patients with metastatic breast cancer [22]. Importantly, a similar enhancement of clinical cardiotoxicity has not been observed when docetaxel is coadministered with doxorubicin [150]. However, taxanes can cause cardiotoxicity as single agents as well. Paclitaxel may cause sinus bradycardia in up to 30% of patients, although this rarely results in significant symptoms, while more serious arrhythmias such as conduction blocks or ventricular tachycardia can develop in up to 5% of treated patients [146, 151]. Complete heart block [152] and myocardial infarction [153] are rare but serious complications associated with taxane treatment. However, cardiac abnormalities caused by taxanes are typically asymptomatic and transient [153]. For these reasons, routine cardiac monitoring is not necessary for patients without preexisting cardiac risk factors, but monitoring is recommended for those with preexisting heart disease [152].

9.11 Hormone Therapies Breast cancer patients are often treated with some form of hormonal therapy in the adjuvant setting, depending upon the level of expression of hormonal receptors identified in tumor biopsy specimens. Such regimens usually consist of tamoxifen (an estrogen receptor antagonist) or aromatase inhibitors (which block the synthesis of estrogen). Several large trials have demonstrated an LDL cholesterol lowering effect of tamoxifen in breast cancer patients compared with placebo-treated or aromatase inhibitor-treated patients, suggesting a potential protective effect of tamoxifen [154]. Consistent with such an effect, women treated with tamoxifen had 50% fewer serious (grades 3–5) ischemic cardiac events compared with those treated the aromatase inhibitor letrozole [155]. However, in

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the same study, tamoxifen treatment was associated with a two-fold increase in thromboembolic events (p < 0.001) compared with letrozole-treated patients. As further evidence of a pro-thrombotic effect of tamoxifen, 1.2% of women with breast cancer treated with tamoxifen developed VTE compared with 0.5% of placebo treated controls [156]. The risk of thromboembolism due to tamoxifen is highest in older women and in the first 2  years of therapy, while the addition of chemotherapies to treatment regimens does not affect risk [156]. Hormonal therapy also has an important role in the treatment of patients with metastatic prostate cancer. Diethylstilbestrol (DES), a synthetic estrogen showed promise in the treatment of metastatic prostate cancer, but at higher dosages (5 mg/day), was found to result in an excess number of cardiovascular deaths compared to placebo, defined as death from myocardial infarction, stroke, heart failure, or pulmonary embolism [157]. Importantly, at lower dosages of DES (1 mg/day), a significant anticancer benefit is observed without an increase in cardiovascular deaths [158]. When used at this dosage, VTE remains the principal toxicity of DES and appears to occur in spite of prophylactic anticoagulation regimens that include low dose warfarin and aspirin [159]. The optimal prophylactic antithrombotic regimen in patients treated with DES has not yet been established. Another form of hormone therapy is androgen deprivation therapy for prostate cancer patients. This is achieved using several strategies, including orchiectomy, treatment with GnRH agonists, or treatment with antiandrogens. Patients treated with GnRh agonists had significantly more cases of diabetes, coronary artery disease, myocardial infarction, and sudden cardiac death than untreated patients [160, 161]. GnRh agonists increase fat mass and fasting insulin levels, and decrease insulin sensitivity [161], providing a mechanistic basis for this increased risk.

9.12 Other Miscellaneous Drugs 9.12.1 Bortezomib Bortezomib is a reversible proteasome inhibitor, resulting in cells accumulating poly-ubiquitylated proteins and eventually triggering apoptosis. It is used

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to treat multiple myeloma and non-small-cell lung cancer [162]. A 2007 study revealed an unexpected increase of cardiac complications in patients with multiple myeloma or non-Hodgkin’s lymphoma on bortezomib alone or in combination. Eight of 69 patients in the study developed serious cardiac effects, including heart failure and arrhythmias, requiring hospitalization or pacemaker implantation [163]. In contrast, the incidence of cardiac events in a large, phase III trial comparing bortezomib with dexamethasone for the treatment of multiple myeloma did not identify an excess of cardiac toxicity in the bortezomib-treated group and reported an incidence of heart failure of 2% in both treatment arms [164]. Since routine cardiac monitoring (e.g., echocardiography, electrocardiography, or clinical assessment by a cardiologist) was not mandated in this trial, the incidence of cardiac toxicity due to bortezomib may be underestimated. Importantly, the incidence of fatigue (a nonspecific symptom of cardiac failure) was significantly greater in the bortezomib-treated group despite a superior objective anticancer response compared with dexamethasone. Thus, the clinical significance of cardiac toxicity due to bortezomib remains unclear and will only be resolved with a prospective study with close cardiac monitoring. Cardiac toxicity due to bortezomib and other proteosome inhibitors is mechanistically plausible. The ubiquitin-proteasome system is crucial for the proper regulation of protein degradation within cardiomyocytes, and abnormalities in the proteasomal pathways and accumulation of damaged proteins are well recognized in several forms of cardiac failure [164]. In addition, a number of pre-clinical studies have linked proteosome inhibition with impaired protein quality control in the vascular endothelium, leading to accelerated atherosclerotic lesion formation [165, 166]. While the clinical significance of these findings is being explored, patients being treated with bortezomib who have preexisting heart disease or significant atherosclerotic risk factors should be closely monitored and receive therapies designed to reduce their cardiovascular risk.

9.12.2 Thalidomide Thalidomide, though most well known for its teratogenic effects, is currently in use for treatment of many solid organ and hematological cancers,

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particularly multiple myeloma. Thalidomide is an antiangiogeneic therapy that inhibits TNFa and modulates the immune system [167]. It has been linked with high incidences of deep venous thrombosis – up to 58% of patients experience an event in some drug combinations. More commonly reported incidences range from 12% to 20% [95]. Lower extremity thrombosis and pulmonary embolism are the most common manifestations, but cerebral venous sinus thrombosis, unstable angina, myocardial infarction, and stroke have also been reported [167]. Possible mechanisms of this adverse effect include inhibition of Cox2, overstimulation of immune response, and modulation of adhesion molecules [95]. Thalidomide acts directly on vascular endothelial cells, particularly those that have been previously damaged [167]. A structural analog of thalidomide, lenalidomide, is associated with similar toxicity. Both drugs are recommended to be used with prophylactic anticoagulant therapies [95].

9.12.3 Interferon-a High-dose interferon is used to treat cutaneous melanoma and other malignancies [168]. Two studies (one of Kaposi’s sarcoma patients and one of chronic myelogenous leukemia) both revealed increased rates of cardiomyopathy associated with interferon therapy [88]. The most common adverse effects reported are transient hypotension, atrial extrasystoles, and suptraventricular arrhythmias, but lethal arrhythmias, myocardial infarction, and dilated cardiomyopathy have also been described [168]. Reported incidence of arrhythmias is up to 20% [54], but incidence of other cardiac effects may be underreported due to similarity of symptoms with more common interferon side effects [88]. Pathology of interferon-treated myocardium shows no myocyte necrosis or anticardiac antibodies, with ultrastructural findings of endothelial tubuloreticular structures (this is an interferon signature) [88]. Interferon may damage endothelial cells, thicken capillary walls, and induce deposition of immune complexes. An inflammatory mechanism has been proposed to play a role in interferon cardiomyopathy [88, 168]. The most effective treatment of cardiac complications is discontinuation of interferon therapy [88].

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9.12.4 Arsenic Trioxide Arsenic trioxide is an effective treatment for relapsed or refractory acute promyelocytic leukemia, but it can cause cardiotoxicity usually manifesting as QT prolongation [169]. Arsenic prolongs action potential duration in the heart, which can also lead to tachyarrhythmias or sudden death [170]. Patients can also develop torsades de pointes or vascular leak syndrome [171]. The toxicity profile in children is similar to that in adults [171], with up to 63% of patients experiencing QT prolongation [54]. Risk factors for development of conduction abnormalities include hypomagnesaemia, hypokalemia, and hypocalcaemia [171]. Prior chemotherapy-induced cardiac damage may also contribute to increased incidence of cardiotoxicity [170]. Patients treated with arsenic who develop QT prolongation should be monitored for arrhythmias, and any electrolyte imbalances in these patients should be corrected before proceeding with therapy [172]. Possible mechanisms of arsenic cardiotoxicity include alterations in DNA methylation and repair, generation of reactive oxygen species, changes in cardiac ion channels, and apoptosis [169]. Apoptosis has been observed in a cell culture model of arsenic cardiotoxicity with caspase-3 activation, intracellular calcium overload, and increased reactive oxygen species [173]. Inhibition of caspase-3, or treatment with vitamin E or verapamil (both antioxidants) alleviated the apoptotic phenotype in this model, suggesting a possible cardioprotective mechanism [173]. Resveratrol, an antioxidant with antiapoptotic and antiarrhythmic effects, was also cardioprotective: concurrent treatment prevented QT prolongation, decreased myocardial injury, inhibited production of reactive oxygen species, and reduced the number of apoptotic cells [169].

9.12.5 IL-2 Interleukin-2 is used at high doses to treat metastatic melanoma and renal cell carcinoma [174]. Hemo­ dynamic alterations including severe hypotension and tachyarrhythmias are frequently observed adverse effects of IL-2 [175]. Treatment-related deaths occur in only 1.5% of patients, but serious complications including myocardial ischemia and myocarditis have

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been reported [176]. Histopathologic analysis suggests a diffuse lymphocytic and eosinophilic form of myocarditis with myocyte necrosis [177]. Capillary leak syndrome, which causes vascular permeability and hypotension, is observed in the majority of IL-2 patients, with vasopressor treatment required in 30–50% [178]. Case reports of more rare cardiotoxicities include global myocardial dysfunction [179], regional aneurysmal and dyskinetic cardiomyopathies [175], and acute myocardial infarction [176]. In addition to an inflammatory cardiomyopathy, direct myocardial toxicity may be due to myocardial stunning accompanied by excessive production of nitric oxide [175]. In an animal model, IL-2 treatment caused myocyte vacuolization, myofibrillar loss, swelling of endothelial cells, migration of lymphocytes into the interstitium, and interstitial hemorrhage and edema [180]. These results suggest that IL-2 activates lymphocytes that first attack endothelial cells, then cardiac myocytes, causing lesions in both cardiac vessels and the myocardium itself [180].

9.13 Cardiotoxicity as a Discovery Platform The value of studying cardiotoxic drugs is not limited to identifying the mechanisms of cardiotoxicity itself. Cardiotoxic effects of molecularly targeted anticancer therapies can shed light on the function of signaling pathways whose role in regulating cardiovascular function was previously unknown. Following such a discovery paradigm, researchers can discover new pathways that are important to the maintenance of adult human cardiac structure and function. Eventually this information may lead not just to better therapeutic strategies for cancer patients with cardiotoxicity, but also to therapies for diseases like cardiomyopathies and ischemic heart disease that are among the most common causes of death in our society. For example, as described above, the monoclonal anti-ErbB2 antibody trastuzumab was found to cause cardiotoxic effects, particularly when combined with anthracyclines. This result was surprising when it first appeared in the clinical trial data because previously ErbB2 was known to be required for embryonic heart development, but expression was thought to be too low

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to be relevant in the adult heart [210]. Recognition of trastuzumab’s cardiotoxicity led to the development of a conditional cardiac-specific knockout mouse model of ErbB2, which has a progressive dilated cardiomyopathy phenotype, and these mice also are more sensitive to anthracycline treatment than wild-type mice [181]. Pressure overload in the rat heart leads to decreased levels of ErbB2 signaling as hypertrophic responses develop into cardiomyopathy, suggesting a protective role of this signaling pathway [27]. Further work on these mice and their cells revealed an important role for ErbB2 signaling in cardiomyocyte survival and mitochondrial function [182]. More recent functional studies have concluded that impaired ErbB2-neuregulin signaling does not consistently lead to apoptosis in vivo, but suggests an interaction instead with neurohormonal regulatory systems. Neuregulin synthesis by endothelial cells appears to be regulated by epinephrine, angiotensin, endothelin, and mechanical stress [183]. Treatment with neuregulin (the ErbB ligand) prolongs survival in several animal models of cardiomyopathies [184]. Clinical trials testing the efficacy of neuregulin as a therapeutic for patients with cardiomyopathy are currently ongoing. The initial evidence of neuregulin-ErbB2 signaling as a cardioprotective pathway emerged as a result of the surprising finding of cardiotoxicity from the antiErbB2 antibody in trastuzumab. The result is a better understanding of the heart itself and a new potential therapeutic target for cardiomyopathy in humans. This same paradigm can be applied to cardiotoxicity caused by other targeted therapies to build a more complete picture of cardioprotective signaling pathways and further our understanding of human heart disease.

9.14 Conclusion Treatment of cardiovascular complications of cancer or cancer therapies first relies on identifying the underlying problem. Excluding nontreatment-related causes of cardiovascular damage suggests that cardiotoxicity of one or more agents in the patient’s treatment regimen is at fault. For many of these drugs, cardiac effects are reversible upon discontinuation of treatment, so this should be the first step undertaken. After

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resolving or stabilizing the cardiovascular disease, rechallenge with the same drug or a change in the treatment regimen can be considered depending on the circumstances. Treatment of cardiomyopathy caused by cardiotoxicity should begin with preventative treatments in those patients at greatest risk. In patients undergoing treatment with potentially cardiotoxic anticancer therapy, we propose that such patients can be classified as stage A patients (at risk for heart failure) per the recently established guidelines for the prevention and treatment of heart failure from the American Heart Association/ American College of Cardiology [60] (see Fig.  9.1). Such guidelines recommend patients receive aggressive treatment for risk factors for cardiovascular disease including diabetes, smoking, hypertension, and hyperlipidemia [49]. Patients who develop asymptomatic cardiac dysfunction (the stage B patient) should be treated with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or beta-blockers [185, 186]. More aggressive drug and/or device treatments are reserved for patients with symptomatic cardiac dysfunction [1]. For patients with myocardial ischemia, treatment with calcium channel blockers or nitrates can be helpful. Prophylactic vasodilators are sometimes used when rechallenging with a drug that produced ischemia, but may not always be effective [187]. It can be especially challenging to treat acute myocardial infarctions in cancer patients, since many cancer therapies cause a high rate of adverse effects like thrombocytopenia that significantly complicate or prevent use of typical therapies [142]. Aspirin therapy does provide a substantial survival benefit, even in patients with thrombocytopenia, so its use is recommended in most patients with acute myocardial infarction [188], and statin therapy is also usually safe and effective in these patients [189]. For most other cardiac effects, including arrhythmias, QT prolongation, hypertension, and thromboembolism, there are limited specific guidelines for treatment in patients with cancer [190]. Caution and monitoring in patients with higher than average risk are the best ways to detect cardiovascular complications. Treatment should be undertaken as with any other patient, but with an awareness of the patient’s other disease and treatment-based toxicities in mind. Cardiovascular diseases are a considerable worry for cancer survivors. As reviewed here, many cancer

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At Risk for Heart Failure STAGE A At high risk for HF but without structural heart disease or symptoms

e.g., Patients with: -hypertension -atherosclerotic disease -diabetes -obesity -metabolic syndrome or Patients -using cardiotoxins -with FHx CM

THERAPY GOALS -Treat hypertension -Encourage smoking cessation -Treat lipid disorders -Encourage regular exercise -Discourage alcohol intake, illicit drug use -Control metabolic syndrome DRUGS -ACEI or ARB in appropriate patients (see text) for vascular disease or diabetes

Structural heart disease

Heart Failure

STAGE B Structural heart disease but without signs or symptoms of HF.

STAGE C Structural heart disease with prior or current symptoms of HF.

e.g., Patients with: -previous MI -LV remodeling including LVH and low EF -asymptomatic valvular disease

e.g., Patients with: -known structural heart disease and -shortness of breath and fatigue, reduced exercise tolerance

Development of HF symptoms

STAGE D Refractory HF requiring specialized interventions.

Refractory symptoms of HF at rest

e.g., Patients who have marked symptoms at rest despite maximal medical therapy (e.g., those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions)

THERAPY THERAPY GOALS -All measures under Stage A DRUGS -ACEI or ARB in appropriate patients (see text) -Beta-blockers in appropriate patients (see text) DEVICES IN SELECTED PATIENTS -Implantable defibrillators

GOALS -All measures under Stages A and B -Dietary salt restriction DRUGS FOR ROUTINE USE -Diuretics for fluid retention -ACEI -Beta-blockers DRUGS IN SELECTED PATIENTS -Aldosterone antagonist -ARBs -Digitalis -Hydralazine/nitrates DEVICES IN SELECTED PATIENTS -Biventricular pacing -Implantable defibrillators

THERAPY GOALS -Appropriate measures under Stages A, B, C -Decision re: appropriate level of care OPTIONS -Compassionate end-oflife care/hospice -Extraordinary measures • heart transplant • chronic inotropes • permanent mechanical support • experimental surgery or drugs

Fig. 9.1  AHA Guidelines for the Classification and Treatment of Congestive Heart Failure. Stages in the development of heart failure/recommended therapy by stage. Cancer patients treated with potentially cardiotoxic chemotherapy (reviewed within) are at risk for the development of heart failure and should be treated according to the treatment recommendations for stage A patients.

Reprinted with permission from the American Heart Association. HF heart failure, FHx CM family history of cardiomyopathy, ACEI angiotensin-converting enzyme inhibitor, ARB angiotensin receptor blocker, MI myocardial infarction, LVH left ventricular hypertrophy, EF ejection fraction

therapies cause significant cardiotoxicity, and in some cases those effects may be underestimated due to the nature of clinical trials. Clinicians should be watchful for early signs or symptoms of cardiotoxicity in their patients. Prevention and treatment of these adverse effects is crucial, and more work needs to be done to define methods of prevention and optimize treatment in the specific population of cancer survivors. Research into the mechanisms of cardiotoxicity will help better identify prevention strategies, as well as enhancing our scientific knowledge of how these drugs work.

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113 156. Hernandez RK, Sørensen HT, Pedersen L, Jacobsen J, Lash TL (2009) Tamoxifen treatment and risk of deep venous thrombosis and pulmonary embolism: a Danish populationbased cohort study. Cancer 19:4442–4449 157. Byar DP (1973) Proceedings: The Veterans Administration Cooperative Urological Research Group’s studies of cancer of the prostate. Cancer 32:1126–1130 158. Brawer MK (2006) Hormonal therapy for prostate cancer. Rev Urol 8(Suppl 2):S35–S47 159. Montgomery RB, Nelson PS, Lin D, Ryan CW, Garzotto M, Beer TM (2007) Diethylstilbestrol and docetaxel: a Phase II study of tubulin active agents in patients with metastatic, androgen-independent prostate cancer. Cancer 110:996–1002 160. Keating NL, O’Malley AJ, Smith MR (2006) Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 24:4448–4456 161. Saylor PJ, Keating NL, Smith MR (2009) Prostate cancer survivorship: prevention and treatment of the adverse effects of androgen deprivation therapy. J Gen Intern Med 24(Suppl 2):S389–S394 162. Voortman J, Giaccone G (2006) Severe reversible cardiac failure after bortezomib treatment combined with chemotherapy in a non-small cell lung cancer patient: a case report. BMC Cancer 6:129 163. Enrico O, Gabriele B, Nadia C et  al (2007) Unexpected cardiotoxicity in haematological bortezomib treated patients. Br J Haematol 138:396–397 164. Richardson PG, Sonneveld P, Schuster MW et  al (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487–2498 165. Herrmann J, Lerman LO, Lerman A (2010) On to the road to degradation: atherosclerosis and the proteasome. Cardiovasc Res 85:291–302 166. Herrmann J, Saguner AM, Versari D et al (2007) Chronic proteasome inhibition contributes to coronary atherosclerosis. Circ Res 101:865–874 167. Rajkumar SV (2005) Thalidomide therapy and deep venous thrombosis in multiple myeloma. Mayo Clin Proc 80:1549–1551 168. Benjamini O, Kimhi O, Lishner M (2007) Severe pleuropericarditis and cardiomyopathy induced by high dose interferon alpha-2b. Isr Med Assoc J 9:486–487 169. Zhao X-Y, Li G-Y, Liu Y et al (2008) Resveratrol protects against arsenic trioxide-induced cardiotoxicity in vitro and in vivo. Br J Pharmacol 154:105–113 170. Vizzardi E, Zanini G, Antonioli E, D’Aloia A, Raddino R, Cas LD (2008) QT prolongation: a case of arsenical pericardial and pleural effusion. Cardiovasc Toxicol 8:41–44 171. Fox E, Razzouk BI, Widemann BC et  al (2008) Phase 1 trial and pharmacokinetic study of arsenic trioxide in children and adolescents with refractory or relapsed acute leukemia, including acute promyelocytic leukemia or lymphoma. Blood 111:566–573 172. Ohnishi K, Yoshida H, Shigeno K et al (2000) Prolongation of the QT interval and ventricular tachycardia in patients treated with arsenic trioxide for acute promyelocytic leukemia. Ann Intern Med 133:881–885 173. Zhao X, Feng T, Chen H et  al (2008) Arsenic trioxideinduced apoptosis in H9c2 cardiomyocytes: implications in

114 cardiotoxicity. Basic Clin Pharmacol Toxicol 102: 419–425 174. Eisner RM, Husain A, Clark JI (2004) Case report and brief review: IL-2-induced myocarditis. Cancer Invest 22:401–404 175. Du Bois JS, Udelson JE, Atkins MB (1995) Severe reversible global and regional ventricular dysfunction associated with high-dose interleukin-2 immunotherapy. J Immunother Emphasis Tumor Immunol 18:119–123 176. Kragel AH, Travis WD, Steis RG, Rosenberg SA, Roberts WC (1990) Myocarditis or acute myocardial infarction associated with interleukin-2 therapy for cancer. Cancer 66:1513–1516 177. Samlowski WE, Ward JH, Craven CM, Freedman RA (1989) Severe myocarditis following high-dose interleukin-2 administration. Arch Pathol Lab Med 113:838–841 178. Acquavella N, Kluger H, Rhee J et al (2008) Toxicity and activity of a twice daily high-dose bolus interleukin 2 regimen in patients with metastatic melanoma and metastatic renal cell cancer. J Immunother 31:569–576 179. Goel M, Flaherty L, Lavine S, Redman BG (1992) Reversible cardiomyopathy after high-dose interleukin-2 therapy (1991). J Immunother 11:225–229 180. Zhang J, Yu ZX, Hilbert SL et al (1993) Cardiotoxicity of human recombinant interleukin-2 in rats. A morphological study. Circulation 87:1340–1353 181. Crone SA, Zhao Y-Y, Fan L et al (2002) ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 8:459–465 182. Grazette LP, Boecker W, Matsui T et al (2004) Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes: implications for herceptin-induced cardiomyopathy. J Am Coll Cardiol 44:2231–2238 183. Lemmens K, Doggen K, De Keulenaer GW (2007) Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure. Circulation 116:954–960 184. Doggen K, Ray L, Mathieu M, Mc Entee K, Lemmens K, De Keulenaer GW (2009) Ventricular ErbB2/ErbB4 activation and downstream signaling in pacing-induced heart failure. J Mol Cell Cardiol 46:33–38 185. Demetri GD, von Mehren M, Blanke CD et  al (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480 186. Felker GM, Thompson RE, Hare JM et al (2000) Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 342: 1077–1084 187. Patel B, Kloner RA, Ensley J, Al-Sarraf M, Kish J, Wynne J (1987) 5-Fluorouracil cardiotoxicity: left ventricular dysfunction and effect of coronary vasodilators. Am J Med Sci 294:238–243 188. Sarkiss MG, Yusuf SW, Warneke CL et al (2007) Impact of aspirin therapy in cancer patients with thrombocytopenia and acute coronary syndromes. Cancer 109:621–627 189. Cannon CP, Braunwald E, McCabe CH et  al (2004) Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 350:1495–1504

A.Y. Khakoo and C.S. Kwartler 190. Yeh ETH, Bickford CL (2009) Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol 53:2231–2247 191. Perik PJ, Rikhof B, de Jong FA, Verweij J, Gietema JA, van der Graaf WTA (2008) Results of plasma N-terminal pro B-type natriuretic peptide and cardiac troponin monitoring in GIST patients do not support the existence of imatinibinduced cardiotoxicity. Ann Oncol 19:359–361 192. Turrisi G, Montagnani F, Grotti S, Marinozzi C, Bolognese L, Fiorentini G (2009) Congestive heart failure during imatinib mesylate treatment. Int J Cardiol 193. Todorova V, Vanderpool D, Blossom S et  al (2009) Oral glutamine protects against cyclophosphamide-induced cardiotoxicity in experimental rats through increase of cardiac glutathione. Nutrition 25:812–817 194. Yeh ETH, Tong AT, Lenihan DJ et al (2004) Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation 109:3122–3131 195. Hacihanefioglu A, Tarkun P, Gonullu E (2008) Acute severe cardiac failure in a myeloma patient due to proteasome inhibitor bortezomib. Int J Hematol 88:219–222 196. Ferrajoli A, O’Brien SM, Cortes JE et al (2003) Phase II study of alemtuzumab in chronic lymphoproliferative disorders. Cancer 98:773–778 197. Fisher B, Costantino JP, Wickerham DL et  al (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 90:1371–1388 198. Chu TF, Rupnick MA, Kerkela R et al (2007) Cardiotoxicity associated with the tyrosine kinase inhibitor sunitinib. Lancet 370:2011–2019 199. Khoury HJ, Guilhot F, Hughes TP, Kim D-W, Cortes JE (2009) Dasatinib treatment for Philadelphia chromosomepositive leukemias: practical considerations. Cancer 115:1381–1394 200. Yamaguchi K, Kanazawa S, Kinoshita Y, Muramatsu M, Nomura S (2005) Acute myocardial infarction with lung cancer during treatment with gefitinib: the possibility of gefitinib-induced thrombosis. Pathophysiol Haemost Thromb 34:48–50 201. Law H (1996) Chemotherapy-induced myocardial infarction. Eur Heart J 17(6):966 202. Smith I (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. New Engl J Med 353:2747–2757 203. Coombes RC, Hall E, Gibson LJ et al (2004) A randomized trial of exemestane after 2 to 3 years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081–1092 204. Arai Y, Tadokoro J, Mitani K (2005) Ventricular tachycardia associated with infusion of rituximab in mantle cell lymphoma. Am J Hematol 78(4):317–318 205. Perez-Verdia A, Angulo F, Hardwicke FL, Nugent KM (2005) Acute cardiac toxicity associated with high-dose intravenous methotrexate therapy: case report and review of the literature. Pharmacotherapy 25:1271–1276 206. Judson I, Radford JA, Harris M et al (2001) Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/ CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC

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115 209. de Nigris F, Rienzo M, Schiano C, Fiorito C, Casamassimi A, Napoli C (2008) Prominent cardioprotective effects of third generation beta blocker nebivolol against anthracycline-induced cardiotoxicity using the model of isolated perfused rat heart. Eur J Cancer 44:334–340 210. de Azambuja E, Bedard PL, Suter T, Piccart-Gebhart M (2009) Cardiac toxicity with anti-HER-2 therapies-what have we learned so far? Target Oncol 4:77–88

 

Prophylaxis: Peace of Mind?

10

Benoit Guery and Karine Faure

Contents References............................................................................ 119

B. Guery (*) and K. Faure Service de Gestion du Risque Infectieux et des Vigilances, CHRU Lille, Hôpital Calmette, Pavillon Christiaens, Lille Cedex 59037, France e-mail: [email protected]

In 2005, Bucaneve et al. reported the results of a randomized placebo-controlled double-blind trial showing that prophylactic levofloxacin given to cancer patients with chemotherapy-induced neutropenia significantly decreased the rate of febrile episodes [1]. However, mortality was not affected, and the long-term ecological impact of levofloxacin prophylaxis was not assessed [1]. Over the following years, many studies assessed the impact of antibiotic selection pressure on microbial ecology. In a prospective study done in a hematology unit, routine levofloxacin prophylaxis was associated with increases in the rates of enterococci, Streptococcus viridans, and Pseudomonas aeruginosa [2]. Another study also found an increase in S. viridans with levofloxacin prophylaxis [3]. These changes in bacterial ecology did not affect mortality rates. In several studies, the implementation of routine levofloxacin prophylaxis was followed by increases in the incidence of fluoroquinolone-resistant gram-negative bacterial strains [4, 5]. Interestingly, these changes had no impact on the incidence of gram-negative infections in the treated population. Other studies found no impact on bacterial ecology. In patients with febrile neutropenia compared to a retrospective cohort in the USA, levofloxacin prophylaxis decreased the rate of gram-negative bacteremia without affecting the rate of gram-positive bacteremia [6]. Neither mortality nor rates of resistance to antibiotics were significantly affected [6]. Studies of emerging resistant strains and antibiotic cycling have supplied useful information. In a prospective cohort of 388 patients in a surgical intensive care unit (ICU), cycling from cefpirome to piperacillin-tazobactam to finally levofloxacin, each molecule used for 4 months, failed to control the emergence of resistant gram-negative strains [7]. In 13 ICUs, selective gastrointestinal tract decontamination, including

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cefotaxime, 4 g/day intravenously for 4 consecutive days, was associated with a significant increase in resistant strains recovered from the respiratory tract [8]. Adding metronidazole to ciprofloxacin-fluconazole for selective gastrointestinal decontamination in patients undergoing allogeneic bone marrow transplantation increased the rate of fungal gastrointestinal colonization but not the rate of invasive fungal infections [9]. We will not discuss the efficacy of selective gastrointestinal decontamination, which remains highly controversial in some patient populations. The reader is referred to the abundant literature on the topic. Prophylactic antibiotic therapy affects bacterial ecology not only at the level of patient populations, but also at the level of hospital departments. Similar changes have been found in response to prophylactic antifungal treatment. Pooled data from two large studies of prophylactic posaconazole, itraconazole, or fluconazole in allogeneic BMT recipients or patients with acute myelogenous leukemia showed that the number of cultures positive for Candida albicans decreased with all three drugs [10]. In contrast, C. glabrata-positive cultures increased significantly with posaconazole and itraconazole therapy, and C. krusei-positive cultures increased significantly with fluconazole therapy. However, the rate of invasive fungal infection during prophylactic antifungal therapy was extremely low (about 1%). Other studies also found evidence of C. glabrata emergence during fluconazole therapy [11]. On the opposite, a study performed in Sweden to assess curative-dose fluconazole in patients with acute leukemia found a significant decrease in invasive fungal infections with no emergence of non-albicans Candida strains but with an increase in gram-positive bacterial infections [12]. No relation was found between fluconazole use over an 11-year period (1994– 2004) and the ratio of albicans/non-albicans Candida strains in a university hospital, despite a high level of fluconazole consumption (defined daily doses, 5,013–6,807/100,000 patient-days [13]). Conflicting data have also been obtained in ICUs. Over a 2-year period, fluconazole prophylaxis was associated with a significant decrease in invasive fungal infections but had no impact on mortality [14]. The flora was not extensively studied, and the potential impact of fluconazole use on fungal ecology was not assessed. A 2006 systematic review and meta-analysis of randomized controlled trials of fluconazole or

B. Guery and K. Faure

ketoconazole prophylaxis in non-neutropenic ICU patients identified 12 trials [15,16]. Invasive infections decreased, and no significant increase in resistant strains was noted. However, the authors pointed out that the trials were not adequately powered to rule out an increase in resistant strains [15,16]. Another metaanalysis published 1 year earlier also found that antifungal prophylaxis was effective without increasing the proportion of resistant strains [17]. Thus, the potential impact of antifungal prophylaxis on fungal ecology remains unclear. The many studies published in recent years produced somewhat conflicting data [18–20]. In addition to the selection of resistant strains, infection prophylaxis may promote the occurrence of opportunistic infections by selecting rare pathogens resistant to the prophylactic agents used. For instance, posaconazole prophylaxis of fungal infections in high-risk patients has been associated with the emergence of ­zygomycosis [21–23] and Scedosporium infections [24]. The last few years have witnessed profound changes in our medical practice. Advances in the management of many diseases have led to the emergence of highrisk patient populations. Thus, intensive chemotherapy regimens and aggressive supportive care generate immune system impairments associated with a high risk of infection. Prophylactic interventions targeting bacterial and fungal infections seem reasonable in these patients. Several studies have highlighted a number of important points. First, long-term effects must be assessed in uniform patient populations. Second, although some studies found increased resistance rates after prophylactic therapy, with no impact on mortality, most studies were not designed to assess changes in resistance rates. Finally, the body of available evidence indicates that antibacterial or antifungal prophylactic therapy modifies the microbial ecology, thereby leading to the emergence of new risks. A crucial point is to weigh the benefits – often measured as decreases in infection rates or, preferably, in mortality rates – against the rate and severity of new infectious complications. In available studies, the amount of detail on the expected benefits contrasts with the uncertainty surrounding the risks, as designing studies to assess risks is challenging. Infection prophylaxis has considerably benefited the management of high-risk patients. However, we will be able to assess the risk/benefit ratio only when detailed information on the long-term impact of infection prophylaxis becomes available.

10  Prophylaxis: Peace of Mind?

References   1. Bucaneve G, Micozzi A, Menichetti F et al (2005) N Engl J Med 353:977–987   2. Cattaneo C, Casari S, Bracchi F et al (2010) Scand J Infect Dis 42:324–332   3. Timmers GJ, Dijstelbloem Y, Simoons-Smit AM et al (2004) Bone Marrow Transplant 33:847–853   4. Kern WV, Klose K, Jellen-Ritter AS et al (2005) Eur J Clin Microbiol Infect Dis 24:111–118   5. Sahagún Pareja J, Castillo FJ, Andrés R et al (2005) Revista espanola de quimioterapia: publicacion oficial de la Sociedad Espanola de Quimioterapia, vol 18, pp 32–38   6. Craig M, Cumpston AD, Hobbs GR et  al (2007) Bone Marrow Transplant 39:477–482   7. van Loon HJ, Vriens MR, Fluit AC et al (2005) Am J Respir Crit Care Med 171:480–487   8. Oostdijk E, De Smet A, Blok H et al (2010) Am J Respir Crit Care Med 181:452–457   9. Trenschel R, Peceny R, Runde V et al (2000) Bone Marrow Transplant 26:993–997 10. Mann P, McNicholas P, Chau A et  al (2009) Antimicrob Agents Chemother 53:5026–5034 11. Tumbarello M, Sanguinetti M, Trecarichi E et  al (2008) J Antimicrob Chemother 62:1379–1385 12. Nihtinen A, Anttila VJ, Elonen E et al (2008) Eur J Haematol 80:391–396

119 13. Blot S, Janssens R, Claeys G et  al (2006) J Antimicrob Chemother 58:474–477 14. Faiz S, Neale B, Rios E et al (2009) Eur J Clin Microbiol Infect Dis 28:689–692 15. Playford EG, Webster AC, Sorrell TC et  al (2006) J Antimicrob Chemother 57:628–638 16. Playford EG, Webster AC, Sorrell TC et al (2006) Cochrane Database of Systematic Reviews (Online) CD004920 http:// onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/ CD004920/frame.html 17. Cruciani M, de Lalla F, Mengoli C (2005) Intensive Care Med 31:1479–1487 18. Bassetti M, Ansaldi F, Nicolini L et al (2009) J Antimicrob Chemother 64:625–629 19. Magill SS, Swoboda SM, Shields CE et al (2009) Ann Surg 249:657–665 20. Manzoni P, Leonessa M, Galletto P et  al (2008) Pediatr Infect Dis J 27:731–737 21. Mousset S, Bug G, Heinz W et al (2009) Transpl Infect Dis 12:261–264 22. Kishel J, Sivik J (2008) J Oncol Pharm Pract 14:189–193 23. Schlemmer F, Lagrange-Xélot M, Lacroix C et  al (2008) Breakthrough Rhizopus infection on posaconazole prophylaxis following allogeneic stem cell transplantation. Bone Marrow Transplant 42:551–552 24. Ananda-Rajah M, Grigg A, Slavin M (2008) Mycopathologia 166:83–86

 

Part Diagnostic Strategy in HM Patients

III

 

How Type of Malignancy and Treatment Assist in the Etiological Diagnosis

11

Alexandre Boyer and Didier Gruson

Contents 11.1 Introduction............................................................. 123 11.2 Risk Factors for Acute Respiratory Failure......... 124 11.2.1 Neutropenia.............................................................. 124 11.2.2 Deficiencies in Cellular and Humoral Immunity................................................... 124 11.2.3 Allogeneic Bone Marrow and Stem Cell Transplantation......................................................... 124 11.3 Bacterial Pneumonia.............................................. 125 11.4 Fungal Pneumonia.................................................. 126 11.5 Viral Pneumonia..................................................... 126 11.6 Noninfectious Causes of Acute Respiratory Failure................................................. 127 11.6.1 Pulmonary Edema..................................................... 127 11.6.2 Pulmonary Toxicity Syndrome................................. 127 11.6.3 Diffuse Alveolar Hemorrhage.................................. 127 11.6.4 Idiopathic Pneumonia Syndrome.............................. 127 11.6.5 Graft-Versus-Host Disease........................................ 128 11.6.6 Bronchiolitis Obliterans............................................ 128 11.6.7 Pulmonary Alveolar Proteinosis............................... 128 11.7 Conclusion............................................................... 128 References............................................................................ 128

A. Boyer and D. Gruson () Medical Intensive Care Unit, Hôpital Pellegrin-Tripode, Place Amélie Raba Léon, 33076, Bordeaux cedex, France e-mail: [email protected]

11.1 Introduction Acute respiratory failure (ARF) in cancer patients is a major cause of morbidity and mortality. The number of cancer patients managed for ARF has increased with the prevalence of cancer and use of bone marrow transplantation (BMT) [1]. Identifying the cause of ARF improves patient outcomes [2, 3]. Many causes of ARF exist in cancer patients, and several causes may be present in the same patient, raising diagnostic challenges. The type of immune deficiency affects the risk of specific pulmonary complications and varies with the type of malignancy and cytotoxic drug exposure, which are therefore useful for guiding the diagnostic strategy [4]. This point is particularly important for diagnosing infections. Cancer chemotherapy severely affects the components of both humoral and cellular immunity, including monocytes/macrophages, neutrophils, the complement cascade, immunoglobulin production, and T lymphocytes. The risk of infection is particularly high when neutropenia develops as a result of cytotoxic chemotherapy or of bone marrow involvement by a hematological malignancy. B-lymphocyte dysfunction due to chemotherapy, bone marrow transplantation, or lymphoproliferative disorders is associated with bacterial infections, whereas T-lymphocyte dysfunction or steroid therapy is associated with viral and fungal infections and with infections due to intracellular bacteria. This chapter reviews the diagnosis of infectious and noninfectious causes of ARF in cancer patients.

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11.2 Risk Factors for Acute Respiratory Failure

11.2.3 Allogeneic Bone Marrow and Stem Cell Transplantation

11.2.1 Neutropenia

After BMT, specific complications tend to occur within well-defined time periods, which facilitates the diagnosis. In general, three periods are defined after allo­ geneic BMT or stem cell transplantation: the preengraftment phase, the postengraftment phase, and the late posttransplantation phase. ARF is more common after allogeneic BMT than after autologous transplantation. Allogeneic BMT requires conditioning followed by chronic treatment with several immunosuppressive agents to prevent or treat graft-versus-host disease (GVHD). Furthermore, GVHD causes immune system impairments by affecting the mucosal surfaces and reticuloendothelial system. In addition, several noninfectious causes of ARF are related to GHVD, such as idiopathic pneumonia syndrome, chronic airway disease, bronchiolitis obliterans, and the engraftment syndrome. After both allogeneic and autologous BMT or stem-cell transplantation, rapid immune system reconstitution may promote the development of inflammatory pulmonary complications. Severe immune dysfunction is present following BMT. The profound neutropenia related to high-dose cytotoxic chemotherapy and total body irradiation lasts 2–4  weeks, and the deficiency in humoral immunity lasts 6  months. During this period, 30% of patients require ICU admission for life-threatening ARF, which is often due to noninfectious diseases. During the preengraftment phase after allogeneic BMT, i.e., for the first 2–4 weeks after the conditioning regimen, severe neutropenia may promote the development of lung infections due to extracellular bacteria and opportunistic fungi. Aspergillus spp. is the most common cause of fungal infections at this phase, whereas Fusarium spp., Cryptococcus neoformans, Candida spp., and Mucormycosis are less common. Other major pulmonary complications during these first 4  weeks include diffuse alveolar hemorrhage, pulmonary edema, and drug-related pulmonary toxicity. The postengraftment phase covers the second and third months after allogeneic BMT. During this period, the neutrophil count begins to increase, but major deficiencies in cellular and humoral immunity persist. Initially, donor lymphocytes may convey passive T-cell immunity, which is partially effective for

Neutropenia related to myelosuppressive chemotherapy or the disease itself is a major risk factor for lung infections in immunocompromised patients. As the leukocyte count decreases, the risk of infection increases. Neutrophils are involved in the phagocytosis of microorganisms, and neutropenia is therefore chiefly associated with infections by extracellular ­pyogenic bacteria and fungi [5]. Common culprits in patients with ARF and fever during the phase of ­neutropenia include Streptococcus pneumoniae, Streptococcus viridans, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella spp., and Escherichia coli. The risk of bacterial infection is highest early in the neutropenic phase. Fungal lung infections (Aspergillus sp., Fusarium, and Candida spp.) are more common after a prolonged period of neutropenia and in patients with complex immune deficiencies (e.g., allogeneic BMT or exposure to the new targeted chemotherapeutic agents such as antiCD52 antibodies).

11.2.2 Deficiencies in Cellular and Humoral Immunity The B-lymphocytes, which are antibody-secreting plasma cells, are the main immune cells affected in lymphoproliferative disorders and after immunosuppressive therapy or allogeneic BMT. B-lymphocyte impairments cause deficiencies in humoral immunity that may lead to lung infections because of S. pneumoniae or gram-negative organisms. Cellular immunity is mediated by the T-lymphocytes. Cellular immunity is impaired in patients with lymphoproliferative disorders, those taking cancer chemotherapeutic agents or steroids, and after BMT. Patients with T-cell dysfunction are susceptible to unusual pathogens such as viruses, protozoa (Toxoplasma gondii), fungi (Aspergillus spp., P. jirovecii, Candida spp.), and bacteria (Legionella pneumophila, Nocardia asteroides, Listeria monocytogenes and mycobacteria).

11  How Type of Malignancy and Treatment Assist in the Etiological Diagnosis

approximately 2 months. Host lymphocytes that survive radiation therapy and chemotherapy may also provide limited cellular immunity during this period. The immune system impairments are greatest after native immunity and passive donor immunity are lost and before immune function is restored by the transplanted marrow. GVHD further increases the immune deficiencies and delays the recovery of normal immune function. At this phase, cytomegalovirus (CMV) is the most common cause of infection, followed by other viruses and by protozoa. The late phase after allogeneic BMT starts after the third month. Recovery of cellular and humoral immunity occurs gradually. During this period, chronic GVHD may delay the recovery of normal immune function. Chronic GVHD occurs in more than 30% of patients after allogeneic BMT and impairs intrinsic immunity. Both infectious and noninfectious diseases may occur. Encapsulated bacteria and P. jiroveci are the main causes of pulmonary infection, and bronchiolitis obliterans and organizing pneumonia may cause acute and chronic pulmonary dysfunction.

11.3 Bacterial Pneumonia During the early stages of immune compromise, bacteria are the most common causes of lung infection in cancer patients. Predisposing factors include bacteremia, disruption of mucosal barriers, defective ciliary function in the tracheobronchial tree, aspiration, and endotracheal intubation. Routine early administration of empiric broad-spectrum antibiotics in febrile neutropenic patients has decreased the incidence of bacterial pneumonia. Bacterial pneumonia may occur at any time after transplantation, but is particularly prevalent during the preengraftment period characterized by profound neutropenia. Bacterial pneumonia develops in about 15% of patients after BMT. Nearly half the cases occur within the first 100 days after BMT and, overall, 22% of cases are fatal. Patients with cancer are at increased risk for gramnegative pneumonia. In patients who are ill or hospitalized, the oropharynx becomes colonized with gram-negative bacilli that are more virulent than the normal flora. Gram-negative pathogens, especially P. aeruginosa and K. pneumoniae, predominate in the

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first 100 days, whereas gram-positive organisms such as S. pneumoniae cause most of the infections seen later on [6]. Legionella spp. has been reported to be an important cause of nosocomial pneumonia in some centers [7, 8]. Among gram-negative organisms, Pseudomonas spp. is a common cause of pneumonia in neutropenic patients. There are increasing reports of pneumonia due to gram-positive microorganisms in immunocompromised patients, a trend that is probably ascribable to the widespread use of indwelling central venous catheters. S. pneumoniae has become more common in neutropenic patients and as a late infection after allogeneic BMT with chronic GVHD. Of growing concern is the rise of antibiotic-resistant strains of S. pneumoniae. S. viridans is increasingly common in leukemia patients with severe oropharyngeal mucositis following high-dose cytarabine therapy. Nocardia asteroides is an opportunistic bacterium that occurs in patients with impaired cellular immunity. Neutropenia is usually not present, but a history of steroid therapy is common. The nodules may be single or multiple, and cavitation may occur. The masslike infiltrate may extend to the pleura, causing a pleural effusion. N. asteroides may also involve the skin, brain, and meninges. Bacterial pneumonia is commonly heralded by a fever, although the usual respiratory symptoms and signs may be absent in neutropenic hosts. The chest X-ray abnormalities may be subtle or absent, probably because of the paucity of neutrophils. In one series, high-resolution computed tomography revealed evidence of pneumonia in more than 50% of febrile neutropenic patients with normal chest X-rays [9]. Broad-spectrum antibiotics (with antipseudomonal activity) should be initiated expeditiously in all patients with suspected bacterial pneumonia and in febrile neutropenic patients with no identified site of infection. There is currently no consensus on the routine use of prophylactic antibiotics in afebrile asymptomatic neutropenic patients during the preengraftment period [10]. Intravenous immunoglobulin therapy may reduce the risk of bacterial infections in the subset of allogeneic BMT recipients who experience severe hypogammaglobulinemia during the first 100 days [10]. In nonendemic areas, tuberculosis is rare after BMT, with a frequency of only 0.1–0.25% in two large surveys [11]. For this book, Dr. El Anazi has produced a comprehensive analysis of tuberculosis in patients

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with hematological malignancies. Risk factors for developing tuberculosis include allogeneic BMT, total body irradiation, and chronic GVHD [12]. Infection with nontuberculous mycobacteria has generally been uncommon among BMT recipients, except with the use of T cell-depleted marrow grafts [12].

11.4 Fungal Pneumonia Pulmonary fungal infections are a major cause of death in immunocompromised patients. In this book, two chapters (by Dr. Bougnoux and Dr. Nucci) focus on invasive fungal pneumonia in patients with hematological malignancies. Neutropenic patients are at risk for opportunistic infections with Aspergillus spp., Candida spp, C. neoformans, and Mucor spp. Reactivation of indolent infection with organisms, such as Histoplasma and Coccidioides, may be seen in patients with impaired cellular immunity. Invasive aspergillosis is among the most devastating complications of allogeneic BMT and is the most common cause of fungal pneumonia in neutropenic patients. Aspergillus infection has been reported in up to 20% of patients after BMT. Risk factors for invasive aspergillosis include prolonged neutropenia, steroid therapy, broad-spectrum antibiotics, GVHD, and transplantation of T cell-depleted marrow. Recipients of both allogeneic and autologous BMT are at increased risk for invasive aspergillosis during the preengraftment phase, when neutropenia is the main risk factor. During the postengraftment period, the risk of invasive aspergillosis remains high after allogeneic BMT. During this period, immunosuppressive agents must be given and GVHD may develop. There has been a notable decline in preengraftment infections, probably because the introduction of hematopoietic growth factors and peripheral bloodstem-cell donation has shortened the period of neutropenia. In contrast, there has been an increase in the frequency of postengraftment infections caused by Aspergillus spp. These risk factors are reported in detail in the chapter by Dr. Bougnoux et al. Other causes of fungal pneumonia are far less common in cancer patients. Emerging fungal infections are covered in the chapter by Dr. Nucci. The zygomycetes, including Mucor and Rhizopus, rarely cause invasive fungal infections after BMT (prevalence of up to 2% of patients). Mucor occurs

A. Boyer and D. Gruson

o­ ccasionally in patients with neutropenia, lymphoproliferative disorders, and prior antibiotic therapy. Risk factors include severe and prolonged neutropenia, steroid-treated acute or chronic GVHD, and severe transfusion-related iron overload. Other ­emerging fungal pathogens that occasionally cause pulmonary infections include Fusarium and Scedos­porium spp. Pneumocystis jiroveci, first identified as a protozoan nearly 100 years ago by C. Chagas and reclassified as a fungus in 1988, is a major cause of pneumonia and ARF in patients with impaired cellular immunity. A chapter of this book focuses on P. jiroveci infection. Most cases are associated with HIV infection rather than with lymphoproliferative disorders, immunosuppressive therapy, or stem-cell transplantation. P. jiroveci infection has rarely been reported in patients with myelodysplastic syndromes. P. jiroveci pneumonia is more common in patients with hematological malignancies compared to those with solid tumors. However, patients with brain tumors from carcinomatous lymphangitis receiving high-dose steroid therapy are at risk for P. jiroveci pneumonia.

11.5 Viral Pneumonia Respiratory viruses can cause severe pneumonia in patients with hematological malignancies [13–17]. A chapter by Dr. Schnell et  al. covers pulmonary involvement by common respiratory viruses. Respiratory syncytial virus, influenza A and B viruses, and parainfluenza viruses are well-documented causes of severe respiratory morbidity and mortality, especially after BMT or hematopoietic stem-cell transplantation. Although lymphopenia is the main risk factor for viral pneumonia, screening for respiratory viruses should be incorporated into the routine diagnostic workup of patients with hematological malignancies until more clinical data become available [18]. The new multiplex PCR tests need further evaluation. Adenovirus infection is an uncommon cause of pneumonia that almost invariably develops within the first 3 months after BMT. CMV can still cause viral pneumonia after allogeneic BMT. For this book, Dr. Vigil and coworkers contributed a very comprehensive review of CMV pneumonia. Although CMV pneumonia usually starts

11  How Type of Malignancy and Treatment Assist in the Etiological Diagnosis

50–60 days after BMT, the onset may occur at any time during the postengraftment phase (50–100  days after transplantation). After BMT, 10–40% of patients experience CMV pneumonia, which is fatal in 85% of cases. Among BMT recipients who are seropositive for CMV, 70% experience CMV infection because of reactivation of latent endogenous virus; among patients who are seronegative for CMV, approximately 36% experience CMV infection. Risk factors for CMV pneumonia include seropositivity in the recipient, seropositive donor and seronegative recipient, older age, total body irradiation, severe acute GVHD, frequent blood transfusions, and use of anti-rejection drugs causing T-cell depletion. Patients with chronic GVHD appear particularly prone to late-onset CMV pneumonia. Herpes simplex virus is a less common cause of viral pneumonia, affecting fewer than 5% of BMT patients. The infection generally occurs during the period of profound neutropenia within 3  weeks after BMT. Idiopathic interstitial pneumonia associated with other herpes viruses (HHV6) has been reported in BMT patients. This book has a chapter on herpes pneumonia, written by Dr. Shah and co-workers.

11.6 Noninfectious Causes of Acute Respiratory Failure Noninfectious conditions have accounted for an increased proportion of ARF cases among cancer patients since the introduction of prophylactic measures against bacterial, fungal, and viral infections [19]. Noninfectious causes of ARF include cardiogenic pulmonary edema, drug-related pulmonary toxicity, and pulmonary alveolar proteinosis. Most of these complications emerge during the first 3 months after stem-cell transplantation. The main pathogenic mechanisms are activation of the inflammatory cascades and T-cell alloreactivity.

11.6.1 Pulmonary Edema Hydrostatic pulmonary edema is a common early complication that is related to the large amounts of intravenous fluids needed to administer antibiotics, blood

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products, cytotoxic drugs (anthracyclin), and parenteral nutrition [20]. Noncardiogenic edema during the preengraftment phase after BMT is often ascribable to lung injury from chemotherapy or total body irradiation combined with episodes of sepsis. Cardiac dysfunction and pulmonary edema may be exacerbated by the development of acute renal failure due to the cancer, drug-related tubular toxicity, or malignant cell lysis.

11.6.2 Pulmonary Toxicity Syndrome This nonspecific syndrome is a manifestation of chemotherapy-induced lung injury. Lung biopsy findings are consistent with drug-related pulmonary toxicity. Chemotherapy regimens well known to be associated with lung injury and ARF are those containing carmustine or high-dose cyclophosphamide or methotrexate.

11.6.3 Diffuse Alveolar Hemorrhage Diffuse alveolar hemorrhage may develop in patients with newly diagnosed or treated myeloblastic leukemia, most notably after autologous or allogeneic BMT or stem-cell transplantation [21, 22]. Profound thrombocytopenia is common in these patients, but is not the cause of the bleeding, which is ascribable to inflammation caused by the influx of neutrophils in the lungs.

11.6.4 Idiopathic Pneumonia Syndrome This idiopathic syndrome defined as diffuse lung injury in the absence of infection is a diagnosis of exclusion [23]. It may be a manifestation of pulmonary toxicity related to pretreatment regimens, especially conventional high-dose conditioning regimens including total body radiation. Other risk factors are malignancy other than leukemia, older age, and high-grade acute GHVD. It is difficult to eliminate an immune-mediated injury because of the frequent association with GHVD. This fact suggests alloreactive T-cell-mediated alveolar injury.

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11.6.5 Graft-Versus-Host Disease GVHD is an immune reaction resulting from minor incompatibilities between the donor and the recipient of an HLA-matched transplant. The donor T lymphocytes recognize the recipient’s tissue as a foreign body. Within the first 100 days after allogeneic BMT or stem cell transplantation, acute GVHD develops in 25–75% of patients. Acute GVHD primarily affects the skin, liver, and gastrointestinal tract, whereas the lungs are rarely involved. Chronic GHVD is more likely to cause ARF than is acute GHVD. In addition, infections and lymphoid interstitial pneumonia may cause ARF in patients with GVHD. Histologically, pulmonary GVHD may manifest as diffuse alveolar damage, lymphocytic interstitial pneumonia, lymphocytic bronchitis, and/or bronchiolitis obliterans.

11.6.6 Bronchiolitis Obliterans Bronchiolitis obliterans is an obstructive pulmonary disorder affecting the small airways. It is a late complication of allogeneic BMT or stem-cell transplantation (5–10%), and is rare in autologous transplant recipients. Bronchiolitis obliterans is associated with chronic GHVD. Although the cause of bronchiolitis obliterans remains unclear, an autoimmune process affecting the small ­airways in the setting of GHVD is suspected [24–27].

11.6.7 Pulmonary Alveolar Proteinosis Alveolar proteinosis is characterized by the deposition in the alveoli of a granular, extracellular, PAS-positive material [28]. This material is a mixture of surfactants, proteins, and lipids. An entire chapter is dedicated to this complication in the Pearl’s section, in the last part of this book.

11.7 Conclusion Patients with cancer and those treated with BMT exhibit a variety of immunological impairments associated with overwhelming opportunistic lung infections, as

A. Boyer and D. Gruson

well as community-acquired pneumonia. The morbidity and mortality from these infections can be high. The organisms most likely to cause pneumonia in immunocompromised patients vary with the nature of the immunological impairment and the period during the course of the immune deficiency.

References   1. Aronchick JM (2000) Pulmonary infections in cancer and bone marrow transplant patients. Semin Roentgenol 35:140–151   2. Benoit DD, Depuydt PO, Peleman RA et  al (2005) Documented and clinically suspected bacterial infection precipitating intensive care unit admission in patients with hematological malignancies: impact on outcome. Intensive Care Med 31:934–942   3. Larché J, Azouley E, Fieux F et al (2003) Improved survival of critically ill cancer patients with septic shock. Intensive Care Med 29:1688–1695   4. Azoulay E, Schlemmer B (2006) Diagnostic strategy in cancer patients with acute respiratory failure. Intensive Care Med 32:808–822   5. Schimpff S (1977) Therapy of infection in patients with granulocytopenia. Med Clin North Am 61:1101–1118   6. Junghanss C, Marr KA, Carter RA et  al (2002) Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoietic stem cell transplantation: a matched control study. Biol Blood Marrow Transplant 8:512–520   7. Clark JG, Crawford SW (1987) Diagnostic approaches to pulmonary complications of marrow transplantation. Chest 91:477–479   8. Harrington RD, Woolfrey AE, Bowden R et  al (1996) Legionellosis in a bone marrow transplant center. Bone Marrow Transplant 18:361–368   9. Heussel CP, Kauczor HU, Heussel G et  al (1997) Early detection of pneumonia in febrile neutropenic patients: use of thin-section CT. AJR Am J Roentgenol 169:1347–1353 10. Sullivan KM, Dykewicz CA, Longworth DL, et al. (2001) Preventing opportunistic infections after hematopoietic stem cell transplantation: the Centers for Disease Control and Prevention, Infectious Diseases Society of America, and American Society for Blood and Marrow Transplantation practice guidelines and beyond. Hematol Am Soc Hematol Educ Program 2001:392–421 11. de la Camara R, Martino R, Granados E et al (2000) Spanish group on infectious complications in hematopoietic transplantation. Tuberculosis after hematopoietic stem cell transplantation: incidence, clinical characteristics and outcome. Bone Marrow Transplant 26:291–298 12. Kotloff RM, Ahya VN, Crawford SW (2004) Pulmonary complications of solid organ and hematopoietic stem cell transplantation. Am J Respir Crit Care Med 170:22–48 13. Cordonnier C, Bernaudin JF, Bierling P et  al (1986) Pulmonary complications occurring after allogeneic bone

11  How Type of Malignancy and Treatment Assist in the Etiological Diagnosis marrow transplantation: a study of 130 consecutive transplanted patients. Cancer 58:1047–1054 14. Soubani AO, Miller KB, Hassoun PM (1996) Pulmonary complications of bone marrow transplantation. Chest 109:1066–1077 15. Wick MR, Moore SB, Gastineau DA et  al (1983) Immunologic, clinical, and pathologic aspects of human graft-versus-host disease. Mayo Clin Proc 58:603–612 16. Kantrow SP, Hackman RC, Boeckh M et  al (1997) Idiopathic pneumonia syndrome: changing spectrum of lung injury after marrow transplantation. Transplantation 63:1079–1086 17. Afessa B, Tefferi A, Litzow MR et al (2002) Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 166:641–645 18. Martino R, Ramila E, Rabella N et  al (2003) Respiratory virus infections in adults with hematologic malignancies: A prospective study. Clin Infect Dis 36:1–8 19. Khurshid I, Anderson LC (2002) Non-infectious pulmonary complications after bone marrow transplantation. Postgrad Med J 78:257–262 20. Hamilton PJ, Pearson ADJ (1986) Bone marrow transplantation and the lung. Thorax 41:497–502 21. Raptis A, Mavroudis D, Suffredini AF et  al (1999) Highdose corticosteroid therapy for diffuse alveolar hemorrhage in allogeneic bone marrow stem cell transplant recipients. Bone Marrow Transplant 24:879–883

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22. Lewis ID, Defor T, Weisdorf DJ (2000) Increasing incidence of diffuse alveolar hemorrhage following allogeneic bone marrow transplantation: cryptic etiology and uncertain therapy. Bone Marrow Transplant 26:539–543 23. Clark JG, Hansen JA, Hertz MI et al (1993) Idiopathic pneumonia syndrome after bone marrow transplantation. Am Rev Respir Dis 147:1601–1606 24. Chan CK, Hyland RH, Hutcheon MA (1990) Pulmonary complications following bone marrow transplantation. Clin Chest Med 11:323–332 25. Jules-Elysee K, Stover DE, Yahalom J et al (1992) Pulmonary complications in lymphoma patients treated with high-dose therapy and autologous bone marrow transplantation. Am Rev Respir Dis 146:485–491 26. Holland KH, Wingard JR, Beschorner WE et  al (1988) Bronchiolitis obliterans in bone marrow transplantation and its relationship to chronic graft-v-host disease and low serum IgG. Blood 72:621–627 27. Paz HL, Crilley P, Patchefsky A et al (1992) Bronchiolitis obliterans after autologous bone marrow transplantation. Chest 102:775–778 28. Cordonnier C, Fleury-Feith J, Escudier E et  al (1994) Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients. Am J Respir Crit Care Med 149:788–794

 

Contribution of Radiology in Patients with Hematological Malignancies and Pulmonary Involvement

12

Claus Peter Heussel

Contents 12.1 Early Detection of Pneumonia............................... 131 12.2 Imaging Techniques................................................ 132 12.2.1 Chest X-Ray............................................................. 132 12.2.2 CT............................................................................. 132 12.2.3 MRI........................................................................... 135 12.2.4 Standard Recommendation....................................... 135 12.3 Infectious Pneumonia............................................. 135 12.3.1 Identifying Pneumonia............................................. 135 12.3.2 Identifying the Cause of Pneumonia........................ 137 12.4 Non-infectious Pulmonary Disease........................ 141 12.4.1 Graft-Versus-Host Disease........................................ 142 12.4.2 Radiation Toxicity.................................................... 142 12.4.3 Drug Toxicity............................................................ 143 12.4.4 Pulmonary Congestion............................................. 144 12.4.5 Leukemic Infiltration................................................ 144 12.4.6 Pulmonary Hemorrhage............................................ 144 12.5 Extrapulmonary Involvement................................ 144 12.6 Conclusion............................................................... 144 References............................................................................ 145

C.P. Heussel Diagnostic and Interventional Radiology, Chest Clinic, Heidelberg University Hospital, Amalienstrasse 5, 69126, Heidelberg, Germany

12.1 Early Detection of Pneumonia In patients with hematological malignancies, infections are associated with high mortality rates, and mortality increases sharply with increasing time to antimicrobial treatment, even within a range of only a few hours [1, 2]. Therefore, early detection of foci of infection is crucial. Furthermore, early detection and treatment of infections may decrease hospital stay length, thereby limiting the cost of treatment. Nonenhanced computed tomography (CT) is about 230€ in Germany (including the interpretation and comparison to previous CT scans). Physical and laboratory findings should be used to determine which organ system or systems are most likely to be involved [3, 4]. The appropriate imaging technique should then be selected with the goal of achieving high sensitivity and a useful negative predictive value [5]. The exact frequencies of organ infections in neutropenic patients are difficult to determine and differ between evidence of microorganisms (colonization), clinically diagnosed infections (patients alive), and infections diagnosed by postmortem examination. Clinically, the lungs are affected in 30% of neutropenic patients with infection. The paranasal sinuses are involved in 3% of these patients overall and in 30% of allogeneic transplant recipients (concomitantly with pneumonia). The gastrointestinal tract, liver, spleen, central nervous system (especially after allogeneic transplantation), and kidneys are rarely affected [6].

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_12, © Springer-Verlag Berlin Heidelberg 2011

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132

12.2 Imaging Techniques

C.P. Heussel

a

12.2.1 Chest X-Ray Chest X-ray (CXR) is widely performed when pneumonia is suspected or must be excluded [7]. Advantages of CXR include rapidity, wide availability (even on the ward), low cost, and low radiation dose. CXR in the supine position can be performed on the ward in isolated neutropenic patients. A major disadvantage of CXR is the occurrence of superimpositions that considerably limit the sensitivity of this method for detecting pneumonia (Figs.  12.1 and 12.2) [8, 9]. In the supine position, lung inflation is limited, and no lateral projection can be obtained, which limits image quality, in addition to other technical issues. In 40 patients with fever of unknown origin after bone-marrow transplantation, digital CXR in the supine position had only 46% sensitivity for early pneumonia detection [10]. Thus, although CXR provides clinically relevant information on central venous catheters (CVC), pleural effusion, and pulmonary congestion [10], it often fails to detect early pneumonia and to rule out pneumonia, two key goals in immunocompromised patients. Therefore, supine CXR alone is not recommended for early pneumonia detection in immunocompromised hosts [11]. Also, when an infiltrate is seen, CXR provides only limited information on its characteristics. Thus, when pneumonia is suspected in an immunocompromised patient, thin-section CT should be preferred at any time, whenever possible [12].

b

c

12.2.2 CT After studies documented the limitations of CXR in patients with hematological malignancies [9], a prospective study compared High resolution CT scan (HRCT) to CXR for early pneumonia detection in 188 neutropenic patients who were still febrile after 48 h on empirical antimicrobial therapy [20]. Patients with normal CXR findings at this time underwent HRCT on the same day, which showed infiltrates in about 60% of cases (Fig. 12.3). During the following days, the diagnosis of pneumonia was confirmed by the microbiological tests or CXR in approximately 50% of these patients (30% of the overall population). In the 40% of patients with normal CXR and HRCT findings at study

Fig.  12.1  Neutropenic febrile patient receiving broad-spectrum antibiotic therapy. CXR was normal on day 3 of fever (a, b). HRCT performed on the same day demonstrated bilateral infiltrates, which were hidden behind the heart on the posterior-anterior projection and obscured by the spine on the lateral projection (c)

12  Contribution of Radiology in Patients with Hematological Malignancies and Pulmonary Involvement

a

c

133

b

d

Fig.  12.2  The small ill-defined nodule in the right upper lobe (c) of this 34-year-old neutropenic patient with acute myelogenous leukemia was not visible on the chest X-ray, even upon retrospective evaluation (a, b). Amphotericin B treatment was started because fungal pneumonia was suspected. However, the

nodule increased in size during neutropenia recovery 2  weeks later (d). To prepare for bone-marrow transplantation, the lesion was resected to prevent spreading. Examination of the specimen showed Aspergillus

inclusion, the rate of pneumonia during follow-up was only 10% [20]. The enrollment of both patients managed using conventional chemotherapy and transplant recipients is a weakness of this study. Another limitation is inherent in the imperfect performance of microbiological testing for diagnosing pneumonia [20]. In addition to detecting pneumonia, ruling out pneumonia is clinically useful. Therefore, the negative predictive value of HRCT has been assessed by determining the rate of, and time to, pneumonia documented by microbiological tests or CXR after a normal HRCT

scan [20]. Pneumonia was rarely found in these patients and was never diagnosed within the first 5 days after a normal HRCT. The rare cases of pneumonia developed later on and were spread over the entire follow-up period (Fig. 12.4). In patients with infiltrates by HRCT, pneumonia was usually documented during the next 5–10 days (Fig. 12.4) [20]. Thus, CT holds considerable promise as a screening technique for pneumonia in neutropenic patients. Sensitivity was 87% and negative predictive value 88%. The discrepancies between HRCT and other

134

C.P. Heussel

a

b

Fig. 12.3  A 45-year-old patient with acute myelogenous leukemia and a history of unrelated peripheral blood stem cell transplantation 6 months earlier. Contrast-enhanced CT demonstrating

npatients

Follow-up after HRCT Neutropenia + CXR normal + empir. ABx HRCT: infiltrate (60%)

90

5 days [11]. Both the early diagnosis and the exclusion of pneumonia are valuable in immunocompromised patients [7].

HRCT: normal (40%)

12.2.2.1 CT Technique

60 112 76 30

61

42

9 0

vessel erosion in a consolidating infiltrate in the left lung. An apposition thrombus is visible in the pulmonary artery of the left lower lobe. She died 2 days later from brain infarction

all

4

39

7

verification by Micro/CXR

Micro

CXR

Fig. 12.4  Number of HRCT scans demonstrating an infiltrate (shaded) or no infiltrate (white) in neutropenic patients with normal same-day CXR findings. The patients were receiving empirical antibiotic therapy (ABx). Pneumonia was diagnosed based on either detection of an infiltrate by CXR or evidence of a relevant microorganism during follow-up after HRCT. Pneumonia diagnosis was very rare after a normal HRCT (white), but was common after an HRCT demonstrating an infiltrate (shaded)

investigations were mainly ascribable to delayed pneumonia after a negative HRCT (classified as false-negative HRCT results) and to minor infiltrates detected by HRCT and treated immediately so that the CXR remained normal (classified as false-positive results). The additional early use of HRCT achieved the diagnosis of pneumonia about 5 days earlier, and a normal HRCT virtually excluded pneumonia during the next

The radiation dose is of limited concern in patients treated with total body irradiation (14,000  mGy) and cytotoxic agents. Current CT techniques deliver 1–10  mSv per lung scan (in this diagnostic scenario, 1 mSv = 1 mGy) [13, 14]. Thus, even when repeated CT scans are performed, the risk of radiation-induced malignancy is low compared to the high mortality associated with the primary malignancy and infections or to the risk of treatment-related secondary malignancies [1]. Terms such as “incremental CT,” “high-resolution CT (HRCT),” “spiral CT,” “thin-section CT,” “multislice CT (MSCT),” and “low-dose CT” are widely used and may confuse non-radiologists. HRCT is an incremental scanning technique with several breathholds. This early technique uses thin sections (e.g., 1 mm) separated by gaps (e.g., 10 mm), resulting in a representative but detailed image of the lungs. However, the non-contiguous scanning limits nodule detection, quantification, and monitoring. The volumetric techniques used in spiral CT and MSCT acquire slices with no gaps, but they are frequently reconstructed using greater slice thickness (e.g., 5 mm), which are associated with spatial volume effects. This characteristic

12  Contribution of Radiology in Patients with Hematological Malignancies and Pulmonary Involvement

limits the detection of inflammatory lung disease, especially ground-glass opacities [15]. Thin-section multislice CT (MSCT), in contrast, allows volumetric scanning and produces detailed images at the same time [16]. Thin-section MSCT is a good technique for monitoring lung disease, since the anatomical position can be accurately replicated from one scan to the next [16]. Given the fast pace of technological developments in the field of CT, the term “CT” is used in the rest of this chapter. In general, contrast enhancement is not necessary for detecting and characterizing pneumonia [12, 17]. In specific situations, however, such as suspected pulmonary embolism or hemoptysis (e.g., due to vessel erosion), CT angiography is beneficial (Fig. 12.5). In allogeneic transplant recipients, bronchiolitis obliterans must be considered [18, 19]. To look for air trapping, a sign of bronchiolitis obliterans, an additional expiratory CT scan is helpful [18, 19].

12.2.3 MRI Magnetic radiography imaging (MRI) has been evaluated for investigating pulmonary ­disease, since it is known to be effective in lesion characterization [21]. An intraindividual comparison showed that, compared to CT, MRI had 95% sensitivity, 88% specificity, 95% positive predictive value, and 88% negative predictive Probability of normal CXR & Micro p < 0.0001, ntot = 188 100%

HRCT: normal n=76

80% n=112 HRCT: infiltrate

60% 10

20

30

135

value [22]. Apart from the absence of radiation exposure (of nearly no benefit in this patient population, as mentioned above), MRI does not help in the early detection of pneumonia (Fig. 12.6). In patients with advanced pneumonia, CT and MRI perform similarly for visualizing the infiltrates [21]. However, CT is widely available, easier, and faster to perform, and less susceptible to breathing artifacts. MRI is superior over CT in detecting abscesses, as central necrosis is visualized clearly on T2-weighted images and rim enhancement after contrast injection on T1-weighted images [21]. Nevertheless, this fact has limited clinical impact. Furthermore, MRI takes longer and requires a higher degree of patient cooperation than does CT. MRI may fail to visualize small lesions, and cardiac motion may limit the detection of lesions adjacent to the left ventricle [22].

12.2.4 Standard Recommendation Identification of the causative organism is considerably more challenging in patients with pneumonia than in those with systemic infections. Attempts to increase the rate of organism recovery failed to significantly improve patient outcomes [23]. Therefore, a widely used strategy in febrile immunocompromised patients is empirical antimicrobial therapy guided by the imaging study results. However, noninvasive testing of sputum, blood, and nasopharyngeal aspirates is both safe and effective, and can be widely used. CT is recommended for the early detection of pneumonia [23]. Importantly, CT findings help to determine whether invasive investigations are in order and which sites they should target. Thus, CT is valuable for guiding bronchoalveolar lavage (BAL) or lung biopsy [54]. Furthermore, CT excludes pneumonia with greater confidence than does CXR. The sequence shown in Fig. 12.7 can be modified if CT capabilities obviate the need for CXR.

40

Time after HRCT until CXR or Micro are positive [d]

Fig.  12.5  Probability of pneumonia diagnosis based on a CXR infiltrate or evidence of a relevant microorganism during followup after HRCT. Kaplan-Meier analysis for patients with normal HRCT scans (grey line) and patients with evidence of pneumonia on HRCT scans (black line). The difference was highly significant (P < 0.0001). Very few cases of pneumonia were diagnosed after a normal HRCT, and the diagnoses were usually made late after HRCT. In patients with infiltrates by HRCT, most pneumonia diagnoses occurred within 5–10 days

12.3 Infectious Pneumonia 12.3.1 Identifying Pneumonia Enlarging infiltrates may develop during hematological reconstitution [24]. Caillot et al. evaluated weekly HRCT findings in 25 neutropenic patients with

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a

b

c

d

Fig. 12.6  Fungal pneumonia. Same-day HRCT and MRI. (a) HRCT findings. (b) MRI, T2-weighted sequence. (c) MRI, non-enhanced T1-weighted gradient-echo sequence. (d) Post-gadolinium MRI. Lesion contrast is similar by CT and contrast-enhanced MRI

Fever >48h

CXR normal CT normal Folloew-up

infiltrate Invasive procedure

Fig. 12.7  Guidelines issued by the Infectious Diseases Working Party (AGIHO) of the German Society of Haematology and Oncology (DGHO) [23]. Since initial CXR is of limited usefulness, this diagnostic step is more and more often omitted and CT performed initially

surgically proven pulmonary aspergillosis [24]. They documented the timing of each pattern and the size of the infiltrates. The halo sign (Fig. 12.8) was visible in 96% of patients on the day of diagnosis (day 0) compared to only 68% on day 3 and dwindling percentages later on. In contrast, cavitation and the more specific air-crescent sign (Fig.  12.9) increased in prevalence over time (from 8% on day 3 to 63% on day 14). Lesion volume increased fourfold from day 0 to day 7 despite successful treatment and neutropenia recovery. The increase in lesion size is probably ascribable to the influx of neutrophils during neutropenia recovery. In critically ill patients, neutropenia recovery has been identified as a risk factor for acute respiratory distress syndrome [8]. In this study [24],

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a

b

c

d

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e

Fig. 12.8  Neutropenic febrile patient with non-Hodgkin lymphoma treated with autologous peripheral blood stem-cell transplantation. On day 2 after transplantation, neutropenia and fever occurred, prompting empirical antifungal treatment (a). Illdefined pulmonary nodules were detected on day 7 (b).

Neutropenia recovery occurred on day 13 when the infiltrate size was greatest (c). Under continuous antifungal treatment and with nearly normal leukocyte counts, the halo faded, and central cavitation developed (d), day 33. The lesions shrank considerably but did not disappear until day 108 (e)

the median time from neutropenia onset to the diagnosis of invasive pulmonary aspergillosis was 19 days. In our study of early HRCT for diagnosing pneumonia in febrile neutropenic patients, the duration of neutropenia was 11  days at pneumonia diagnosis [20].

12.3.2 Identifying the Cause of Pneumonia Ideally, the microorganism causing pneumonia should be identified. However, several days are needed to obtain the results of microbiological and pathological investigations. Furthermore, these investigations fail to

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a

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b

c

Fig. 12.9  The ill-defined nodules with cavitation were detected by CT done to evaluate repeated brief febrile episodes (b). They suggested fungal pneumonia and were not visible on the

baseline CT (a). After port resection, both pulmonary lesions resolved, and no further febrile episodes occurred (c)

recover the organism in some patients [25]. Finally, the recovered organism is not necessarily the cause of the disease. Surface colonization may complicate the interpretation of microbiological results, and superinfection with an additional organism occurs in about 20% of cases [26, 27]. Imaging study findings cannot prove the nature of the pulmonary disease, but may provide valuable clues [28, 29], of which the most useful are listed in Table 12.1. Optimal interpretation of these clues is particularly important, as fever of unknown origin in immunocompromised hosts may be related to a variety of diseases, whose clinical presentations may be closely similar. Therefore, the imaging studies should be read by experienced radiologists, who should work in close collaboration with the clinicians. Radiologists should be informed about patient characteristics, such as neutropenia, allogeneic or autologous transplantation, positive tests for viral disease in the transplant and recipient, and exposure to cytotoxic agents or conditioning regimens (Table 12.1).

neutropenia [27], their empirical treatment has been optimized in recent years. Radiological features may include consolidation, especially in bronchopneumonia, and a positive bronchogram (Table  12.1) [29, 30]. Ground-glass opacities are more common than in immunocompetent patients, but are of course not specific of bacterial infection.

12.3.2.1 Bacterial Pneumonia Since bacteria are responsible for approximately 90% of infections during the early phase of

12.3.2.2 Fungal Pneumonia Persistent fever in neutropenic patients may indicate invasive fungal infection [1]. In Europe, the main causative organism is Aspergillus spp. Rarely, Candida spp. is shown antemortem to be a cause of pneumonia (Fig. 12.10) [11]. Candida isolates may merely indicate surface colonization. The typical findings of fungal and non-fungal pneumonia and of lung infiltrates caused by non-infectious diseases are detailed in a specific review [31]. Radiological studies may show pulmonary infiltrates, ill-defined nodules, and the halo sign at the earliest phase. Cavitation or even the air crescent sign may be visible later on. For clinical and epidemiological research in neutropenic patients, the EORTC and BAMSO defined recommendations for interpreting radiological findings in

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Table 12.1  Clinical and radiological appearance in various infectious and non-infectious lung diseases in neutropenic patients and bone marrow or stem cell transplant recipients Diagnosis Clinical setting Radiological appearance Infection bacterial

Early phase neutropenia

Consolidation, bronchopneumonia positive pneumobronchogram, GGO

Fungal

Prolonged neutropenia

Halo = ill-defined nodules (early phase)consolidations, negative pneumobronchogram

(>10 days)

Air crescent sign/cavitation (late phase) Pneumocystis

Allogeneic transplantation

GGO, sparing of the subpleural space Intralobular septa (late phase)

Tuberculosis

Various

Small, ill-defined nodules/cavitations, tree-in-bud, homogeneous consolidation

Viral

Transplantation

GGO – mosaic pattern

history in graft or host Graft versus host

Allogeneic transplantation

GGO – mosaic pattern Intralobular septa become visible Tree-in-bud Air trapping (expiratory CT)

Radiation toxicity

Total body irradiation

GGO – paramediastinal distribution, also after TBI Intralobular septa become visible

Drug toxicity

Bleomycin, methotrexate, cytarabine, GGO – mosaic pattern carmustine, etc. Intralobular septa become visible Peripheral consolidations of secondary lobule Traction bronchiectasis

Pulmonary congestion

Leukemic infiltration

Extensive hydration, renal impairment, hypoproteinosis

GGO

Chronic leukemic infiltration

Bronchovascular bundle thickening

Interlobular septa become visible

Interlobular septa become visible GGO Pulmonary hemorrhage

Thrombocytopenia, intervention, hemoptysis

GGO Sedimentation phenomenon

GGO ground-glass opacity, TBI total body irradiation

invasive fungal infections in 2002 [32], then issued an update in 2008 [33]. The new occurrence of “typical” CT patterns (dense, well-circumscribed lesions with or without a halo sign, air crescent sign) constitutes a criterion for fungal pneumonia (Figs. 12.9 and 12.10). The halo sign was first described in 1984 [34, 35]. Although promising observations were made in 1986, the halo sign is non-specific [29] and is not required in the 2008 EORTC recommendations [33]. A non-specific

infiltrate was considered a minor criterion in the 2002 recommendations [32], but was dropped in 2008 [33]. In a study of baseline CT findings in 235 patients with invasive pulmonary aspergillosis who were enrolled in a trial of antifungal treatment, presence of the halo sign (143 patients) was associated with a higher response rate (52% vs. 29%; P < 0.001) and with a higher 3-month survival rate (71% vs. 53%; P < 0.01), compared to the 79 patients without a halo sign [36].

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a

d

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b

c

e

f

Fig.  12.10  Bilateral ill-defined nodules suggested a fungal infection (a, b), and antifungal treatment was given. Candida spp. Was identified in blood cultures and suspected as a cause of pneumonia. The small lesions developed into cavitations upon haematological reconstitution (c) then decreased in size (d).

Liver enzyme levels increased, suggesting hepatosplenic candidiasis related to the candidemia. Contrast-enhanced CT showed liver lesions (e), which were biopsied. Candida spp. was found in the biopsy specimens (f)

Major limitations of this study include the use of thicksection CT instead of thin-section CT and the evaluation of hard copies instead of monitor reading [35]. In a study of 31 patients with hematological malignancies and suspected invasive pulmonary aspergillosis based on highly suggestive CT findings, open lung biopsy confirmed this diagnosis in only 17 (53%) patients [37]. The halo sign may be seen in patients with cryptogenic organizing pneumonia (COP, formerly known as bronchiolitis obliterans organizing pneumonia, BOOP), pulmonary hemorrhage, pulmonary involvement by the malignancy, and other infections (e.g., cytomegalovirus, tuberculosis, abscesses, and Candida) (Figs. 12.9 and 12.10) [37]. In sum, the halo sign suggests fungal pneumonia in neutropenic patients, but is not specific. Further diagnostic investigations are therefore in order, particularly when there is no response to antifungal treatment. The air-crescent sign and cavitation develop concomitantly with hematological reconstitution during the late phase of fungal pneumonia [37]. Thus, both findings are associated with a good prognosis. However, they lack specificity, and differential diagnoses should be considered (Figs.  12.9 and 12.10) [38]. Another useful clue to fungal pneumonia is the feeding vessel sign characterized by lesion distribution along the bronchovascular bundle.

Advances in the field of antifungal drugs have affected the radiological appearance of fungal pneumonia. Mycetomas are rare with prophylactic or early antifungal treatment. In the near future radiologists will strive not only to determine whether the findings suggest fungal pneumonia, but also whether they suggest non-Aspergillus fungal pneumonia.

12.3.2.3 Pneumocystis Jiroveci Pneumonia (Pcp) Pneumocystis jiroveci pneumonia (PcP) is not a typical event in patients with hematological malignancies other than lymphoproliferative disorders, except when highdose or prolonged immunosuppressive therapy is used, most notably in allogeneic transplant recipients with chronic graft-versus-host disease [39–43, 54]. With standard trimethoprim/sulfamethoxazole prophylaxis, PcP may develop in about 8% of patients [43]. Prophylaxis is highly effective. In patients with hematological malignancies and PcP, mortality is 4–15% overall and up to 50% in the subset requiring ICU admission [43]. CT is valuable for differentiating PcP from pneumonia due to other organisms [12, 17, 28, 29]. A combination of ground-glass opacities and intralobular septa sparing the subpleural space (i.e., in a perihilar distribution) is very typical for PcP (Fig. 12.11) [29, 44].

12  Contribution of Radiology in Patients with Hematological Malignancies and Pulmonary Involvement

a

b

141

12.3.2.4 Tuberculosis Tuberculosis is a rare but relevant differential diagnosis in patients with hematological malignancies and suspected pneumonia [54]. The features of tuberculosis differ between immunocompromised patients and immunocompetent patients (e.g., primary gangliopulmonary disease) [45]. Immunocompromised patients tend to suffer greater lymphogenic and hematogenous dissemination, which may lead to a fulminant clinical course [45, 46]. Furthermore, tuberculosis may mimic or occur concomitantly with other infections such as pulmonary aspergillosis or systemic candidiasis [46]. In immunocompromised hosts, segmental bronchial spread (resulting in the “tree-in-bud” sign) of small, sometimes cavitated, ill-defined nodules may be seen, as well as military shadows [45, 46]. Primary gangliopulmonary involvement may be seen as heterogeneous consolidation and necrotic mediastinal and hilar lymphadenopathy [45].

12.3.2.5 Viral Pneumonia

c

Interstitial pneumonia in neutropenic patients and, most notably, after neutropenia recovery is frequently caused by a viral infection. Common culprits are cytomegalovirus, herpes viruses, influenza, parainfluenza, adenovirus, and respiratory syncytial viruses. There are no useful radiological patterns for differentiating the various forms of viral pneumonia. However, even a suspicion of viral pneumonia is very valuable information for the radiologist. Appropriate drug regimens are available for many of the causative viruses. The typical appearance of early-stage viral pneumonia is groundglass opacification [29] and a mosaic pattern with affected and non-affected secondary lobules lying adjacent to one another (Fig. 12.12).

12.4 Non-infectious Pulmonary Disease

Fig. 12.11  Bilateral pneumonia caused by Pneumocystis jiroveci (PcP) at different stages of immunosuppression. The subpleural space is typically spared. Diffuse ground-glass opacities typically appear at the early phase of infection (a), while consolidations appear when the disease runs a fulminant course (b). Intralobular linear densities predominate in later stage or treated PcP (c)

Several non-infectious diseases may affect the lungs in patients with hematological malignancies, such as graft-versus-host disease (GvHD), radiation toxicity, drug toxicity, pulmonary congestion, and bleeding. A fever may be related to the malignancy. For instance, in GvHD, the treatment of non-infectious infiltrates differs from that of infectious infiltrates. Thus, differentiating GvHD and infection is very helpful for

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a

Fig. 12.12  Bilateral ground-glass opacities and mosaic pattern in two patients, A and B. However, the causative organism is cytomegalovirus in patient A (a) and respiratory syncytial virus

C.P. Heussel

b

in patient B (b). Note the mosaic pattern produced by affected and non-affected secondary lobules lying adjacent to one another

clinicians. CT can assist in detecting and characterizing non-infectious pulmonary diseases [12, 28].

12.4.1 Graft-Versus-Host Disease Pulmonary manifestations of chronic GvHD occur in approximately 10% of allogeneic transplant recipients, usually about 9 months after the procedure (Fig. 12.13) [47] Bronchiolitis obliterans is among the pulmonary complications of GvHD [18, 54]. Unfortunately, the radiological appearance is similar to that of viral pneumonia, and the clinical signs are not specific. In early stage GvHD, pulmonary imaging may show ground-glass opacities and a mosaic pattern, as well as signs of bronchiolitis obliterans such as air trapping [18, 19] and bronchus wall thickening (Fig.  12.13), whereas intralobular septa and tree-in-bud images develop later on [47, 48].

Fig. 12.13  A 28-year-old male after allogeneic re-transplantation for chronic myelogenous leukemia. HRCT was performed on post-transplantation day 91 to evaluate a fever with a cough and dyspnea. Peripheral intralobular septa (arrow) and groundglass opacities were seen. The tree-in-bud pattern (arrowhead) suggests bronchiolitis obliterans. Acute GvHD was diagnosed by a transbronchial biopsy. The immunosuppressive treatment regimen was stepped up, after which the clinical symptoms and radiological signs disappeared. Note the similarity to Fig. 12.15

12.4.2 Radiation Toxicity Radiation-induced pulmonary toxicity has been reported in 5–25% of patients, even after total body irradiation for conditioning before bone marrow or stem cell transplantation [49]. One problem in

diagnosing radiation toxicity is that the manifestations are delayed, usually by about 3 weeks but occasionally by several months [48, 49]. CT shows ground-glass opacities with transition to consolidations (Fig. 12.14) [48, 49]. The key finding is

12  Contribution of Radiology in Patients with Hematological Malignancies and Pulmonary Involvement

143

may blur the demarcation between exposed and nonexposed regions.

12.4.3 Drug Toxicity

Fig. 12.14  Three weeks after local irradiation for an osteolytic vertebral tumor, this patient started experiencing a fever and dyspnea. Perihilar infiltrates appeared suddenly. HRCT showed intralobular septa, consolidation, and ground-glass opacities. The paramediastinal distribution of the infiltrates strongly suggested radiation pneumonitis. After failure of antibiotic escalation (given because of a concomitant abscess), corticosteroid therapy was added. The symptoms improved promptly and the infiltrates decreased

that these changes are confined to the radiation field. During total body irradiation, the lung parenchyma is protected, and toxicity chiefly involves the paramediastinal and apical regions. However, distortion of the lung parenchyma and the development of adhesions

a

Fig. 12.15  (a) A 40-year-old male given chemotherapy including bleomycin (PEB protocol) for testicular cancer. CT was performed to evaluate a fever with a cough and dyspnea. Peripheral intralobular septa and ground-glass opacities were seen (a). The known pulmonary toxicity of the bleomycin suggested drug tox-

Drug-induced pulmonary toxicity is particularly common with the high doses of cytotoxic agents used for conditioning. Widely used agents include bleomycin, methotrexate, cytarabine, and carmustine (Fig. 12.15) [50]. Radiologists must inform themselves about the cytotoxic agents used in their patients. The term “drug-induced pneumonitis” encompasses several disorders, of which the most common are nonspecific interstitial pneumonia and cryptogenic organizing pneumonia (COP, formerly known as bronchiolitis obliterans organizing pneumonia or BOOP) [50, 54]. The CT appearance of non-specific interstitial pneumonia consists of ground-glass opacities with transition to consolidations, intralobular septa, traction bronchiectasis, air trapping, and at a later stage the non-specific crazy-paving pattern [48, 50]. These findings are similar to those produced by radiation toxicity, but they are not limited to the radiation field. When lung toxicity is suspected but the agent is unclear, valuable information can be obtained from the French website www.pneumotox. com, which has versions in English and Spanish.

b

icity, which was confirmed by an open lung biopsy. Corticosteroid therapy was given. The symptoms resolved and the radiological abnormalities decreased. Note the similarity to Fig. 12.13. (b) In a similar clinical setting, non-specific interstitial pneumonia in a patient given cytarabine for acute myelogenous leukemia

144

C.P. Heussel

12.4.4 Pulmonary Congestion Pulmonary congestion is common even in younger patients, with contributing factors including central venous catheterization, extensive hydration for renal protection during chemotherapy, transient renal function impairment, and low serum protein levels. Pulmonary congestion is among the most common disorders in ICU patients with hematological malignancies. Dyspnea and lung infiltrates are common in patients with pulmonary congestion. CT shows thickening of the lymphatic vessels seen as Kerley lines (Fig. 12.16).

12.4.5 Leukemic Infiltration Leukemic pulmonary infiltration is less common. The perilymphatic pulmonary interstitium is predominantly involved [51]. CT may show thickening of the bronchovascular bundles and interlobular septa. Nonlobular and non-segmental ground-glass opacities may be visible [28]. This pattern may mimic pulmonary congestion (Fig. 12.16).

12.4.6 Pulmonary Hemorrhage In patients with pancytopenia, pulmonary bleeding may occur spontaneously after procedures such as bronchoalveolar lavage or during hematological reconstitution after fungal pneumonia [52]. The bleeding may be focal

Fig.  12.17  Bilateral ground-glass opacities with an anteriorposterior gradient [1] over the entire lung and [2] within some of the secondary lobules. This gravity-dependent sedimentation phenomenon may occur temporarily and may be localized (e.g., after BAL) or a sign of diffuse pulmonary bleeding

or diffuse. Sedimentation within the secondary lobules may be visible for a few days (Fig. 12.17).

12.5 Extrapulmonary Involvement A global clinical approach is mandatory in these highrisk patients. Imaging can investigate liver and spleen for deep-seated infections (Candida, tuberculosis) or specific diseases (GvHD, VOD), gastrointestinal involvement such as infectious (CMV) or specific ­colitis (GvHD), infectious or non-infectious brain involvement. Interestingly since the sinuses are part of the respiratory tract, sinus infection correlates with pneumonia [53]. Sinus infections occur in up to 30% of allogeneic transplant recipients. Bone erosion and orbital or brain invasion are classified in the 2008 EORTC guideline as criteria for probable invasive fungal disease [33].

12.6 Conclusion

Fig. 12.16  Thickening of the intralobular septa related to fluid overload in the lymphatic vessels

Many lung complications may develop in patients with neutropenia, most notably after bone marrow or stem cell transplantation. Supine CXR is not recommended for the early detection of infiltrates in these patients. When pneumonia is suspected, early thin-section CT is advisable, either to identify the cause of the fever (when lesions are seen) or to exclude the occurrence of pneumonia over the next few days (when findings are normal).

12  Contribution of Radiology in Patients with Hematological Malignancies and Pulmonary Involvement

Imaging studies may show features that strongly suggest the nature of the lung disease. Close cooperation between clinicians and radiologists starting before CT scanning, together with careful image interpretation by experienced radiologists, may rapidly provide the etiological diagnosis.

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146 28. Tanaka N, Matsumoto T, Miura G, Emoto T, Matsunaga N (2002) HRCT findings of chest complications in patients with leukemia. Eur Radiol 12:1512–1522 29. Reittner P, Ward S, Heyneman L, Johkoh T, Müller NL (2003) Pneumonia: high-resolution CT findings in 114 patients. Eur Radiol 13:515–521 30. Conces DJ (1998) Bacterial pneumonia in immunocompromised patients. J Thoracic Imaging 13:261–270 31. Heußel CP, Ullmann AJ, Kauczor H-U (2000) Fungal pneumonia. Radiologe 40:518–529 32. Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, Denning DW, Donnelly JP, Edwards JE, Erjavec Z, Fiere D, Lortholary O, Maertens J, Meis JF, Patterson TF, Ritter J, Selleslag D, Shah PM, Stevens DA, Walsh TJ (2002) Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: An International Consensus. Clin Infect Dis 34:7–14 33. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, Pappas PG, Maertens J, Lortholary O, Kauffman CA, Denning DW, Patterson TF, Maschmeyer G, Bille J, Dismukes WE, Herbrecht R, Hope WW, Kibbler CC, Kullberg BJ, Marr KA, Muñoz P, Odds FC, Perfect JR, Restrepo A, Ruhnke M, Segal BH, Sobel JD, Sorrell TC, Viscoli C, Wingard JR, Zaoutis T, Bennett JE (2008) European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group; National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group: Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46:1813–1821 34. Gefter WB, Albelda S, Talbot G, Gerson S, Cassileth P, Miller WT (1984) New observations on the significance of the air crescent in invasive pulmonary aspergillosis. Radiology 153:136 35. Kuhlman JE, Fishman EK, Siegelman SS (1985) Invasive pulmonary aspergillosis in acute leukemia: characteristic findings on CT, the CT halo sign, and the role of CT in early diagnosis. Radiology 157:611–614 36. Greene RE, Schlamm HT, Oestmann JW, Stark P, Durand C, Lortholary O, Wingard JR, Herbrecht R, Ribaud P, Patterson TF, Troke PF, Denning DW, Bennett JE, de Pauw BE, Rubin RH (2007) Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign. Clin Infect Dis 44:373–379 37. Kim K, Lee MH, Kim J, Lee KS, Kim SM, Jung MP, Han J, Sung KW, Kim WS, Jung CW, Yoon SS, Im YH, Kang WK, Park K, Park CH (2002) Importance of open lung biopsy in the diagnosis of invasive pulmonary aspergillosis in patients with hematologic malignancies. Am J Hematol 71:75–79 38. Kim MJ, Lee KS, Kim J, Jung KJ, Lee HG, Kim TS (2001) Crescent sign in invasive pulmonary aspergillosis: frequency and related CT and clinical factors. J Comput Assist Tomogr 25:305–310 39. Saito T, Seo S, Kanda Y, Shoji N, Ogasawara T, Murakami J, Tanosaki R, Tobinai K, Takaue Y, Mineishi S (2001) Early onset Pneumocystis carinii pneumonia after allogeneic

C.P. Heussel peripheral blood stem cell transplantation. Am J Hematol 67(3):206–209 40. Kovacs JA, Hiemenz JW, Macher AM, Stover D, Murray HW, Shelhamer J, Lane HC, Urmacher C, Honig C, Longo DL et al (1984) Pneumocystis carinii pneumonia: a comparison between patients with the acquired immunodeficiency syndrome and patients with other immunodeficiencies. Ann Intern Med 100(5):663–671 41. Zahar JR, Robin M, Azoulay E, Fieux F, Nitenberg G, Schlemmer B (2002) Pneumocystis carinii pneumonia in critically ill patients with malignancy: a descriptive study. Clin Infect Dis 35(8):929–934 42. De Castro N, Neuville S, Sarfati C, Ribaud P, Derouin F, Gluckman E, Socié G, Molina JM (2005 Nov) Occurrence of Pneumocystis jiroveci pneumonia after allogeneic stem cell transplantation: a 6-year retrospective study. Bone Marrow Transplant 36(10):879–883 43. Bollée G, Sarfati C, Thiéry G, Bergeron A, de Miranda S, Menotti J, de Castro N, Tazi A, Schlemmer B, Azoulay E (2007 Oct) Clinical picture of Pneumocystis jiroveci pneumonia in cancer patients. Chest 132(4):1305–1310 44. McGuinness G, Gruden JF (1999) Viral and Pneumocystis carinii infections of the lung in the immunocompromized host. J Thorac Imaging 14:25–36 45. Van Dyck P, Vanhoenacker FM, Van den Brande P, De Schepper AM (2003 Aug) Imaging of pulmonary tuberculosis. Eur Radiol 13(8):1771–1785 46. Goo JM, Im JG (2002) CT of tuberculosis and nontuberculous mycobacterial infections. Radiol Clin North Am 40:73–87 47. Leblond V, Zouabi H, Sutton L, Guillon JM, Mayaud CM, Similowski T, Beigelman C, Autran B (1994) Late CD8+ lymphocytic alveolitis after allogeneic bone marrow transplantation and chronic graft-versus-host disease. Am J Respir Crit Care Med 150:1056–1061 48. Oikonomou A, Hansell DM (2002) Organizing pneumonia: the many morphological faces. Eur Radiol 12: 1486–1496 49. Monson JM, Stark P, Reilly JJ, Sugarbaker DJ, Strauss GM, Swanson SJ, Decamp MM, Mentzer SJ, Baldini EH (1998) Clinical radiation pneumonitis and radiographic changes after thoracic radiation therapy for lung carcinoma. Cancer 82:842–850 50. Erasmus JJ, McAdams HP, Rossi SE (2002) High-resolution CT of drug-induced lung disease. Radiol Clin North Am 40:61–72 51. Heyneman LE, Johkoh T, Ward S, Honda O, Yoshida S, Muller NL (2000) Pulmonary leukemic infiltrates: high-resolution CT findings in ten patients. AJR Am J Roentgenol 174:517–521 52. Heussel CP, Kauczor HU, Heussel G, Mildenberger P, Dueber C (1997) Aneurysms complicating inflammatory diseases in immunocompromised hosts: value of contrastenhanced CT. Eur Radiol 7:316–319 53. Savage DG, Taylor P, Blackwell J et  al (1997) Paranasal sinusitis following allogeneic bone marrow transplant. BMT 19:55–59 54. Lass-Florl C, Resch G, Nachbaur D, Mayr A, Gastl G, Auberger J, Bialek R, Freund MC (2007) The value of computed tomography guided percutaneous lung biopsy for diagnosis of invasive fungal infection in immunocompromised patients. Clin Infect Dis 45:e101–e104

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Christophe Dooms and Vincent Ninane

Contents 13.1 Introduction............................................................. 147 13.2 Is There Still a Place for Transbronchial Lung Biopsy?......................... 148 13.2.1 TBB Increases the Diagnostic Yield of BAL in Non-neutropenic Patients........................ 149 13.2.2 TBB Does Not Increase the Diagnostic Yield of BAL in Patients with Neutropenic Fever or in Patients on Mechanical Ventilation........................................ 149 13.3 Is There Still a Place for CT-Guided Percutaneous Lung Biopsies or Surgical Lung Biopsies?........................................................ 150 13.3.1 CT-Guided Percutaneous Lung Biopsy.................... 150 13.3.2 Open Lung Biopsy.................................................... 150 13.3.3 CT-Guided Lung Biopsy Has a High Diagnostic Yield in Patients with Known Hematological Malignancies and Focal Pulmonary Lesions................................................... 150 13.3.4 The Diagnostic Yield of Surgical Lung Biopsy (SLB) in Patients with Hematological Malignancies and Lung Infiltrates Varies with the Presentation................................................ 151 13.4 Conclusion............................................................... 151 References............................................................................ 152

C. Dooms University Hospitals Leuven, 49, Herestraat, 3000, Leuven, Belgium V. Ninane (*) C.H.U. St Pierre – Clinique de Pneumologie, Saint-Pierre University Hospital Brussels, 322, rue Haute, 1000, Brussels, Belgium e-mail: [email protected], [email protected]

13.1 Introduction With the expanding use of immunosuppression (e.g., hematopoietic stem cell transplantation and high-dose chemotherapy for aggressive malignancies), respiratory and critical care physicians are increasingly providing care to immunocompromised patients. In patients with hematological malignancies, several conditions can cause immunodeficiency, including the malignancy itself (e.g., leukemia or lymphoma); chemotherapy within the last 3 months; long-term corticosteroid therapy (i.e., ³20 mg/day prednisone for ³2 months); high-dose corticosteroid therapy (³60 mg/ day prednisone for ³2 weeks within the last 3 months); bone marrow or stem cell transplantation; and use of immunosuppressive drugs. The clinical presentation of immunocompromised patients with lung infiltrates seems nonspecific. Symptoms consist of shortness of breath, a cough, fever, and, in many cases, progressive hypoxemia. In patients with known immunosuppression, an opportunistic infection is immediately suspected, but many infectious and noninfectious causes should be considered also. Noninfectious processes are responsible for about 25–50% of pulmonary infiltrates in immunocompromised patients [1, 2]. The radiological changes caused by opportunistic infections may be difficult to distinguish from malignant lung infiltration, heart failure, or cancer chemotherapy toxicity. Moreover, radiation therapy, graft-versus-host disease, acute or chronic rejection, and idiopathic pulmonary disorders (i.e., alveolar proteinosis, diffuse alveolar damage, organizing pneumonia, and diffuse alveolar hemorrhage) may also contribute to the development of pulmonary complications in this setting. As an example, in a series of patients with hematological malignancies and lung infiltrates assessed by open

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_13, © Springer-Verlag Berlin Heidelberg 2011

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lung biopsy, infections accounted for only 36% of the specific diagnoses, and 67% of the cases were related to the malignancy or to inflammatory processes [3]. Another retrospective series including 213 patients with hematological malignancies and pulmonary lesions found that computed tomography (CT)-guided percutaneous biopsy provided a specific diagnosis in 60% of cases; the most common specific diagnoses were malignancy (63%) and infection (34%) [4]. In addition, two or more different processes may affect the lung simultaneously in immunocompromised patients. Malignancy is more often the cause of the pulmonary infiltrates in patients with lung lesions but no respiratory signs/symptoms or fever, whereas infection is more common in patients with acute leukemia, neutropenia, ongoing chemotherapy, or bone marrow transplantation. Pulmonary infiltrates are a frequent cause of morbidity and mortality in immunocompromised patients and remain a diagnostic challenge. In a study of HIVnegative immunocompromised patients with pulmonary infiltrates, three factors predicted mortality: severity of illness as measured by the APACHE II score, need for mechanical ventilation, and longer time to a specific diagnosis [5]. A greater than 5day delay in identifying the cause of the pulmonary infiltrates independently increased the risk of death by more than threefold [5]. One hypothesis is that this effect of timeto-diagnosis reflects the fact that noninfectious causes are both more severe and more difficult to diagnose. However, the early diagnosis of both viral and fungal infections has also been shown to decrease mortality [6]. The early etiological diagnosis of focal or diffuse pulmonary infiltrates can be achieved by serological testing (including polymerase chain reaction technologies), sputum analysis, and bronchoscopic techniques, including bronchoalveolar lavage (BAL). Although BAL is the main invasive diagnostic procedure used in immunocompromised patients with pulmonary infiltrates, its diagnostic yield is only about 50% [7], and additional invasive procedures such as transbronchial biopsy (TBB), CT-guided percutaneous lung biopsy, or surgical lung biopsy (SLB) are often considered. These invasive techniques can supply tissue samples measuring about 1 mm to several centimeters in size, which may allow the identification of both infectious and noninfectious processes. No randomized trial comparing invasive and noninvasive tools has been performed in immunocompromised patients. In this

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population, only retrospective and prospective observational studies are available. Pulmonary lesions in patients with hematological malignancies vary in their severity and etiology according to the type of underlying malignancy, clinical presentation, and time of lung lesion discovery during the course of the disease. The efficacy of TBB, CT-guided percutaneous lung biopsy, or SLB depends largely on the clinical setting and radiological pattern of the pulmonary infiltrate.

13.2 Is There Still a Place for Transbronchial Lung Biopsy? As long as BAL remains the cornerstone of the diagnostic evaluation of immunocompromised patients with pulmonary involvement, the role for TBB will be a matter of interest because a forceps can be introduced through the operating channel of the bronchoscope to biopsy peripheral lesions or infiltrates. Several technical aspects and limitations of TBB should, however, be taken into account before discussing the potential of TBB for providing additional information in patients with hematological malignancies. In patients with nodules or masses (but not diffuse involvement), fluoroscopy may be helpful and may increase the diagnostic yield of TBB provided the lesion is larger than 2 cm [8]. Similarly, lung CT may allow site-directed (but not real-time-guided) TBB, which is associated with an increased diagnostic yield (Fig. 13.1) [9]. The size of the forceps used for TBB has an impact, as larger forceps retrieve larger samples that have a higher diagnostic yield with no additional risk of bleeding [10]. One frequent contraindication in these patients is thrombocytopenia, and it is important to stress that TBB can be performed safely after a platelet transfusion [11, 12], although no specific recommendations have been published. As an example, White and colleagues suggested that the platelet count should exceed 30·109/L for TBB [13]. The main complications of TBB are pneumothorax and bleeding, but these are seldom encountered [14]. More often, bronchoscopy is associated with a (temporary) decrease in arterial oxygen tension. Therefore, bronchoscopy has been considered relatively contraindicated when, despite supplemental O2 delivery, PaO2 remains lower than 75 mmHg or oxygen saturation lower than 90% [15].

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Fig. 13.1  A 47-year-old patient presented with fever and elevated liver enzymes 4 months after allogeneic BMT for relapsing AML. He was receiving steroids for acute GVHD (isolated skin involvement for 3 weeks). Liver biopsy was diagnostic of uncontrolled GVHD, and immunosuppressants were increased. CT was diagnostic of an isolated pulmonary nodule. Sputa examinations as well as BAL fluid analysis were negative. Invasive pulmonary aspergillosis was confirmed by trans-bronchial biopsy

Oxygenation strategies maintain sufficient oxygenation during bronchoscopy and increase the safety of bronchoscopy. In selected patients, bronchoscopy and BAL performed using Boussignac continuous positive airway pressure was safe, with no subsequent respiratory deterioration [16]. Safety is crucial since mechanical ventilation required by complications of BAL with TBB is associated with a high mortality rate that tends to override the expected benefit from the procedure [7, 11, 14].

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lymphoma, organizing pneumonia, graft-versus-host disease, radiation-induced pneumonitis, or diffuse alveolar damage). In a retrospective study [18], only 11 of 95 immunocompromised patients with hematological disorders had sufficient platelet counts to allow TBB, but the procedure was diagnostic in 7 (64%) of them. Similarly, a prospective study [1] of 200 immunocompromised patients showed that TBB was performed in only 11  patients but was diagnostic in 6 (55%) of them, most of whom had their treatment changed as a result of the findings. In another prospective study [19], TBB was possible in 45 of 104 immunocompromised patients (46% with hematological malignancies, 60% receiving chemotherapy, and >75% receiving longterm systemic corticosteroid therapy). Overall, BAL had a diagnostic yield of 38%. In the 45 patients who underwent TBB, the diagnostic yield was 44% for TBB and 70% for BAL plus TBB. TBB was the only investigation that provided the diagnosis in 28% of patients, of whom all but two had noninfectious infiltrates. Pneumothorax was the most frequent complication after TBB, with a rate of 4%. In a study evaluating the diagnostic usefulness of adding TBB to BAL in immunocompromised patients with hematological malignancies [20], BAL performed well for diag­nosing infections (particularly fungal infections), whereas combined BAL and TBB was superior over BAL alone  for diagnosing neoplastic infiltrates and toxic pneumonitis.

13.2.1 TBB Increases the Diagnostic Yield of BAL in Non-neutropenic Patients

13.2.2 TBB Does Not Increase the Diagnostic Yield of BAL in Patients with Neutropenic Fever or in Patients on Mechanical Ventilation

In non-neutropenic, non-HIV-infected immunocompromised patients, TBB has been shown to increase the diagnostic yield of BAL by 30% [17–20]. TBB may contribute to the diagnostic yield of BAL both in infectious processes (by allowing histopathological confirmation of cytomegalovirus pneumonitis or granulomatous lung diseases such as tuberculosis) and in noninfectious processes (by allowing histopathological confirmation of underlying malignant infiltration,

In a retrospective study of a population with febrile neutropenia (neutrophils <1,000 ×109/L), including 80% of patients with hematological malignancies [21], more than 75% of all pulmonary infiltrates were attributable to infections. The diagnostic yield of BAL was 49%, and sputum analysis increased the yield to 63%. TBB provided additional information in only 1% of patients. Thus, TBB should be considered of limited usefulness in neutropenic patients.

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A retrospective study in mechanically ventilated immunocompromised patients showed that TBB was diagnostic in 35% of cases, but that the diagnoses (mainly Pneumocystis and CMV pneumonia) would also have been made by BAL [22]. In a small retrospective study, TBB performed during mechanical ventilation was diagnostic in only 31% of immunocompromised patients [23]. In mechanically ventilated patients, TBB is often contraindicated because of the patient’s oxygen requirements or of the procedure’s low sensitivity and high morbidity (40% pneumothorax rate) in severely hypoxemic patients. Recent data indicate that invasive aspergillosis may be underestimated in immunocompromised ICU patients with pneumonia [24]. Early galactomannan detection in BAL was 88% sensitive and 87% specific when a cutoff of 0.5 was used, which was significantly better than fungal culture and/or microscopic BAL examination or galactomannan detection in serum [25].

13.3 Is There Still a Place for CT-Guided Percutaneous Lung Biopsies or Surgical Lung Biopsies? 13.3.1 CT-Guided Percutaneous Lung Biopsy CT-guided percutaneous lung biopsy requires transportation of the patient to the radiology department and may therefore not be the procedure of choice for patients with severe acute respiratory failure and/or mechanical ventilation with high FiO2 values. As with TBB, CT-guided percutaneous lung biopsy can be performed after platelet transfusion to correct low platelet counts, as done in as many as 46 among 213 patients in a recent non-ICU study [4]. The diagnostic yield is up to 60%. However, pneumothorax occurred in 38.5% of cases and required chest tube drainage, usually on an ambulatory basis, a finding that deserves consideration as most of these patients initially had no respiratory signs or symptoms [4].

13.3.2 Open Lung Biopsy Open lung biopsy is believed to be safe and reliable in patients with non-severe events and may be

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associated with a substantial diagnostic yield in those with diffuse lung disease [26]. Video-assisted thoracoscopy is being increasingly used as an alternative to open thoracotomy. In the only prospective randomized study available to date, thoracostomy was not associated with lower morbidity and mortality rates compared to thoracotomy [27]. An open procedure is often preferred in patients with severe hypoxemia. A  bedside 10-cm lateral thoracotomy can be performed in patients with acute respiratory distress syndrome to obtain specimens 3–5 cm in size with no risk of death and with only a small decrease in the PaO2/FiO2 ratio [28].

13.3.3 CT-Guided Lung Biopsy Has a High Diagnostic Yield in Patients with Known Hematological Malignancies and Focal Pulmonary Lesions In a retrospective study of 213 patients, CT-guided percutaneous biopsy provided a specific diagnosis in 60% of patients; the most common specific diagnoses were malignancy (63%) and infection (34%) [4]. Most of these patients had no respiratory signs/symptoms or positive cultures from BAL or TBB specimens, but chest CT disclosed nodules (59%), masses (12%), cavitary lesions (10%), or consolidation (19%). Importantly, biopsies of focal lesions (mainly cavitary lesions or lung masses) had a higher diagnostic yield than biopsies of diffuse lesions. CT-guided percutaneous biopsy yielded a specific diagnosis in 37 (53%) of the 70 patients with a previous non-diagnostic BAL, TBB, or both (but it is unknown whether these procedures were image-guided). In addition, in 14 patients with no specific diagnosis after CT-guided lung biopsy, BAL and TBB were performed and provided a specific diagnosis in only 4 patients, who had positive cultures of BAL or TBB specimens [4]. Other small retrospective studies have confirmed the usefulness of CT-guided transthoracic lung biopsy for the diagnosis of focal pulmonary lesions in patients with hematological malignancies. As an example, in a study of 24 patients with suspected pulmonary infection including 8 patients with hematological malignancies [29], CT-guided needle biopsy of parenchymal

13  Is There Still a Place for Transbronchial Lung Biopsy or Other Lung Biopsy Techniques?

consolidation with or without cavitation identified one or more etiologic microorganisms in 19 (79.2%) patients. Importantly, similar diagnostic yields have been reported using fluoroscopic-guided transthoracic biopsy, without CT [30, 31]. Thus, one possibility is that BAL combined with fluoroscopy-guided TBB [8] during the same procedure may be comparable with CT-guided lung biopsy for the diagnosis of focal lesions in patients with hematological malignancies, while, however, being associated with a lower risk of pneumothorax.

13.3.4 The Diagnostic Yield of Surgical Lung Biopsy (SLB) in Patients with Hematological Malignancies and Lung Infiltrates Varies with the Presentation In general, SLB is considered the reference standard for diagnosing interstitial lung disease. Several recent retrospective studies reassessed the role for SLB in patients with hematological malignancies and lung infiltrates. In one of these studies, 63 patients with hematological malignancies underwent SLB for lung processes of unknown etiology [3]. A specific diagnosis was found in 62% of patients and led to a change in treatment in 57%. Survival rates after 1 and 3 months were also higher in patients with a specific diagnosis. Infections accounted for only 33% of the specific diagnoses and malignancy or inflammatory processes for the remaining 67%. The authors attributed this finding to widespread use of preemptive, prophylactic, and empiric strategies, as well as to the widespread use of invasive bronchoscopic (and other) diagnostic tests. Interestingly, they also studied the relationships between clinical factors and achieving a specific diagnosis. In the seven patients on mechanical ventilation or with neutropenia, SLB provided no specific diagnosis. In addition, a specific diagnosis was less frequently obtained in the group with prior bronchoscopy (n = 35, specific diagnosis in 48%) than in the group without previous bronchoscopy (n = 32, specific diagnosis in 75%). Finally, a focal radiographic pattern was associated with a higher specific diagnosis rate (n = 39; specific diagnosis in 79%) than a diffuse radiographic

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pattern (n = 28; specific diagnosis in 32%), as previously reported in similar patient populations [32, 33]. In another retrospective study [34], 39 immunocompromised patients (including 30 with hematological malignancies) were studied, and a clinical benefit defined as changes in treatment was observed in 46% of the patients; however, the overall mortality rate was high (39%). In a retrospective study [35] in 62 patients with hematological malignancies or hematopoietic stem cell transplantation, SLB provided a specific diagnosis in 67% of patients and led to changes in treatment in 40%. The main specific diagnoses were infection (29%, mainly aspergillosis), malignancy (27%), and inflammatory conditions (11%). Mortality was lower in the patients who had a specific diagnosis. BAL was performed before SLB in 34 (54%) patients and was non-diagnostic in 28. Of the 13 patients on mechanical ventilation, only 4 (30%) had a specific diagnosis. A focal radiographic pattern was not associated with a significantly higher specific diagnosis rate (n = 33; specific diagnosis in 70%) than a diffuse pattern (n = 29; specific diagnosis in 58%). In contrast, in stem cell transplantation recipients with pulmonary infiltrates, SLB findings led to treatment changes in only a few cases, and eight of the nine patients who required mechanical ventilation died [36]. Finally, the impact of bedside open lung biopsies on the management of mechanically ventilated immunocompromised patients with acute respiratory distress syndrome was studied [37]. Among the 19 patients, 10 had hematological malignancies, and most of them had extensive investigations including chest CT and bronchoscopy. SLB provided a specific diagnosis in 13 (68%) patients and prompted major changes in management in 89%. However, 9 of the 13 specific diagnoses consisted in diffuse alveolar damage, which was classified among nonspecific diagnoses in previous studies, and 17 of the 19 patients died in the ICU [3, 35].

13.4 Conclusion A prompt diagnosis seems crucial for improving the survival of immunocompromised patients with pulmonary infiltrates [5, 38]. Pulmonary involvement in patients with hematological malignancies can be due

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to a variety of causes, among which the most common are malignancy and infection. Early noninvasive tests should be performed, with or without invasive tests depending on the clinical presentation. Thoracic CT should be performed routinely before invasive procedures (TBB, CT-guided biopsy, or SLB), as it provides important diagnostic information and may increase the diagnostic yield of the invasive procedure by improving selection of the technique and sampling site. In patients with hematological malignancies who are selected for bronchoscopy with BAL, TBB is a source of additional information in up to 30% of cases and is best performed under fluoroscopic guidance. The diagnostic yield of TBB ranged from 26% to 68% in published studies. Routine TBB is not recommended in immunocompromised patients, due to safety issues and to uncertainty about the clinical relevance of TBB in some situations. In non-neutropenic patients scheduled for diagnostic bronchoscopy, TBB (if not contraindicated) should be combined with BAL in the initial diagnostic workup only when non-infectious causes of lung infiltrates are suspected, to avoid sequential procedures. In neutropenic patients scheduled for bronchoscopy, TBB should not be performed, as it adds little to the diagnostic yield but increases the complication rate. Both CT-guided biopsy and SLB seem relatively safe but are clearly more invasive than BAL plus TBB. Their diagnostic yield is good, most notably in patients who have focal lesions. Studies of SLB suggest that performing a bronchoscopy first may decrease the need for SLB [3]. Thus, the best initial procedure may be BAL with or without TBB under fluoroscopic guidance, in particular in patients with focal lesions. In the ICU and in mechanically ventilated patients, BAL and TBB are not recommended, although they occasionally constitute useful alternatives to SLB. In this setting, TBB has a low diagnostic yield and can cause pneumothorax with potentially severe consequences. CT-guided biopsy should be reserved for selected patients, because it requires patient transportation to the radiology department. Last, SLB is rarely performed because studies clearly suggest a very low diagnostic yield in ICU and mechanically ventilated patients, with a questionable impact on the already elevated morta­ lity rate.

C. Dooms and V. Ninane

References   1. Rano A, Agusti C, Jimenez P et al (2001) Pulmonary infiltrates in non-HIV immunocompromised patients: a diagnostic approach using non-invasive and bronchoscopic procedures. Thorax 56:379–387   2. Torres A, Ewig S, Insausti J et al (2000) Etiology and microbial patterns of pulmonary infiltrates in patients with orthotopic liver transplantation. Chest 117:494–502   3. White D, Wong P, Downey R (2000) The utility of open lung biopsy in patients with hematologic malignancies. Am J Respir Crit Care Med 161:723–729   4. Gupta S, Sultenfuss M, Romaguera J et al (2009) CT-guided percutaneous lung biopsies in patients with haematologic malignancies and undiagnosed pulmonary lesions. Hematol Oncol 28(2):75–81   5. Rano A, Agusti C, Benito N et al (2002) Prognostic factors of non-HIV immunocompromised patients with pulmonary infiltrates. Chest 122:253–261   6. Von Eiff M, Roos N, Schulten R (1995) Pulmonary aspergillosis: early diagnosis improves survival. Respiration 62: 341–347   7. Azoulay E, de Miranda S, Bèle N, Schlemmer B (2008) Stratégie diagnostique dans l’insuffisance respiratoire aiguë des patients d’oncohématologie. Rev Mal Respir 25: 433–448   8. Chechani V (1996) Bronchoscopic diagnosis of solitary pulmonary nodules and lung masses in the absence of endobronchial abnormality. Chest 109:620–625   9. Cadranel J, Gillet-Juvin K, Antoine M, Carnot F, Reynaud P, Parrot A, Carette MF, Mayaud C, Israël-Biet D (1995) Sitedirected bronchoalveolar lavage and transbronchial biopsy in HIV-infected patients with pneumonia. Am J Respir Crit Care Med 52:1103–1106 10. Loube DI, Johnson JE, Wiener D, Anders GT, Blanton HM, Hayes JA (1993) The effect of forceps size on the adequacy of specimens obtained by transbronchial biopsy. Am Rev Respir Dis 148(5):1411–1413 11. Weiss SM, Hert RC, Gianola FJ, Clark JG, Crawford SW (1993) Complications of fiberoptic bronchoscopy in thrombocytopenic patients. Chest 104:1025–1028 12. Papin TA, Lynch JP, Weg JG (1985) Transbronchial biopsy in the thrombocytopenic patient. Chest 88:549–552 13. White P, Bonacum JT, Miller CG (1997) Utility of fiberoptic bronchoscopy in bone marrow transplant patients. Bone Marrow Transplant 20:681–687 14. Pue CA, Pacht ER (1995) Complications of fiberoptic bronchoscopy at a university hospital. Chest 107:430–432 15. American Thoracic Society (1990) Clinical role of bronchoalveolar lavage in adults with pulmonary disease. Am Rev Respir Dis 142:481–486 16. Maitre B, Jaber S, Maggiore SM, Bergot E, Richard JC, Bakthiari H, Housset B, Boussignac G, Brochard L (2000) Continuous positive airway pressure during fiberoptic bronchoscopy in hypoxemic patients. A randomized double-blind study using a new device. Am J Respir Crit Care Med 162:1063–1067 17. Cazzadori A, Di Perri G, Todeschini G et  al (1995) Transbronchial biopsy in the diagnosis of pulmonary infiltrates in immunocompromised patients. Chest 107:101–106

13  Is There Still a Place for Transbronchial Lung Biopsy or Other Lung Biopsy Techniques? 18. Hohenadel I, Kiworr M, Genitsariotis R et al (2001) Role of bronchoalveolar lavage in immunocompromised patients with pneumonia treated with a broad spectrum antibiotic and antifungal regimen. Thorax 56:115–120 19. Jain P, Sandur S, Meli Y et al (2004) Role of bronchoscopy in immunocompromised patients with lung infiltrates. Chest 125:712–722 20. Mulabecirovic A, Gaulhofer P, Auner H et  al (2004) Pulmonary infiltrates in patients with hematologic malignancies: transbronchial lung biopsy increases the diagnostic yield with respect to neoplastic infiltrates and toxic pneumonitis. Ann Hematol 83:420–422 21. Peikert T, Rana S, Edell E (2005) Safety, diagnostic yield, and therapeutic implications of flexible bronchoscopy in patients with febrile neutropenia and pulmonary infiltrates. Mayo Clin Proc 80:1414–1420 22. O’Brien J, Ettinger N, Shevlin D et  al (1997) Safety and yield of transbronchial biopsy in mechanically ventilated patients. Crit Care Med 25:440–446 23. Bulpa P, Dive A, Mertens L et al (2003) Combined bronchoalveolar lavage and transbronchial lung biopsy: safety and yield in ventilated patients. Eur Respir J 21:489–494 24. Meersseman W, Vandecasteele S, Wilmer A et  al (2004) Invasive aspergillosis in critically ill patients without malignancy. Am J Respir Crit Care Med 170:621–625 25. Meersseman W, Lagrou K, Maertens J et  al (2008) Galactomannan in BAL fluid: a tool for diagnosing aspergillus in intensive care unit patients. Am J Respir Crit Care Med 177:27–34 26. Shah SS, Tsang V, Goldstraw P (1992) Open lung biopsy: a safe reliable and accurate method for diagnosis in diffuse lung disease. Respiration 59:243–246 27. Miller JD, Urschel JD, Cox G, Olak J, Young JE, Kay JM, McDonald E (2000) A randomized, controlled trial comparing thoracoscopy and limited thoracotomy for lung biopsy in interstitial lung disease. Ann Thorac Surg 70:1647–1650 28. Papazian L, Thomas P, Bregeon F, Garbe L, Zandotti C, Saux P, Gaillat F, Drancourt M, Auffray JP, Gouin F (1998) Open-lung biopsy in patients with acute respiratory distress syndrome. Anesthesiology 88(4):935–944

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29. Hwang SS, Kim HH, Park SH, Jung JI, Jang HS (2000) The value of CT-guided percutaneous needle aspiration in immunocompromised patients with suspected pulmonary infection. Am J Roentgenol 175(1):235–238 30. Wong PW, Stefanec T, Brown K, White DA (2002) Role of fine-needle aspirates of focal lung lesions in patients with hematologic malignancies. Chest 121:527–532 31. Castellino RA, Blank N (1979) Etiologic diagnosis of focal pulmonary infection in immunocompromised patients by fluoroscopically guided percutaneous needle aspiration. Radiology 132:563–567 32. Catterall JR, McCabe RE, Brooks RG, Remington JS (1898) Open lung biopsy in patients with Hodgkin’s disease and pulmonary infiltrates. Am Rev Respir Dis 139: 1274–1279 33. McCabe RE, Brooks RG, Catterall JR, Remington JS (1989) Open lung biopsy in patients with non-Hodgkin’s lymphoma and pulmonary infiltrates. Chest 96:319–324 34. Kramer MR, Berkman N, Mintz B, Godfrey S, Saute M, Amir G (1998) The role of open lung biopsy in the management and outcome of patients with diffuse lung disease. Ann Thorac Surg 65:198–202 35. Zihlif M, Khanchandani G, Ahmed HP, Soubani AO (2005 Feb) Surgical lung biopsy in patients with hematological malignancy or hematopoietic stem cell transplantation and unexplained pulmonary infiltrates: improved outcome with specific diagnosis. Am J Hematol 78(2):94–99 36. Dunn JC, West KW, Rescorla FJ, Tres Scherer LR, Engum SA, Rouse TM, Smith JW, Grosfeld JL (2001) The utility of lung biopsy in recipients of stem cell transplantation. J Pediatr Surg 36:1302–1303 37. Charbonney E, Robert J, Pache JC, Chevrolet JC, Eggimann P (2009) Impact of bedside open lung biopsies on the management of mechanically ventilated immunocompromised patients with acute respiratory distress syndrome of unknown etiology. J Crit Care 24:122–128 38. Shorr A, Kollef M (2002) The quick and the dead: the importance of rapid evaluation of infiltrates in the immunocompromised patient. Chest 122:9–12

 

The Increasing Role for Core Needle Biopsy of Pulmonary Lesions in Immunocompromised Patients

14

Cédric de Bazelaire, Raphael Calmon, Marion Chapelier, Amélie Pluvinage, and Eric de Kerviler

Contents

14.1 Introduction

14.1 Introduction............................................................. 155

Although immunocompromised patients now have a better prognosis than in the past, they remain exposed to a variety of complications including tumors, infections, and inflammatory or immunological disorders. Many of these complications affect the lungs. The numerous treatments used by immunocompromised patients affect the computed tomography appearance of the lung lesions, thus raising diagnostic challenges. Percutaneous transthoracic needle biopsy is a wellestablished method for achieving the cytological diagnosis of lung lesions that is being increasingly used to solve difficult diagnostic problems. In 1976, Haaga and Alfidi [1] reported that computed tomography (CT) was the most accurate method for guiding percutaneous needle biopsies, and, since then, many studies have shown that percutaneous transthoracic needle biopsy is effective and accurate [2–8]. Diagnostic accuracy was greater than 80% for benign disease and greater than 90% for malignant disease [2–8]. Lung biopsy indications and methods have changed over the years with the increased use of CT and introduction of new treatments for various diseases. Lung biopsy is being increasingly performed. As with all invasive procedures, lung biopsy is associated with morbidity and mortality and, therefore, requires a multidisciplinary discussion to determine whether a biopsy is appropriate and, if so, which method is best. At least a pulmonologist and a radiologist with special expertise in chest diseases should be involved. Factors that weigh heavily on the decision to perform a lung biopsy include the respiratory status and coagulation test results. Fine-needle aspiration biopsy (FNAB) was the first technique used for lung biopsy. However, FNAB yields only cytological specimens. Core needle biopsy using

14.2 Acronyms................................................................. 156 14.3 Techniques............................................................... 156 14.3.1 Preoperative Investigations....................................... 156 14.3.2 Biopsy....................................................................... 157 14.3.3 Sample Conditioning................................................ 160 14.3.4 Safety, Major and Minor Complications.................. 161 14.4 Efficiency................................................................. 165 14.4.1 Sensitivity and Adequacy......................................... 165 14.4.2 Specific Diagnoses.................................................... 168 14.5 Conclusion............................................................... 172 References............................................................................ 172

C. de Bazelaire (*), R. Calmon, M. Chapelier, A. Pluvinage, and E. de Kerviler Service de radiologie, Hôpital Saint-Louis, Université Paris VII, 1 avenue Claude Vellefaux, 75475 Paris Cedex, France e-mail: [email protected]

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_14, © Springer-Verlag Berlin Heidelberg 2011

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cutting needles of similar diameter to those used for FNAB yields tissue cores that can be used for histological studies. In this chapter, the term percutaneous transthoracic needle biopsy refers to core needle biopsy. The purpose of this chapter is to describe percutaneous transthoracic needle biopsy and to discuss the risks and diagnostic performance of this method.

14.2 Acronyms Several acronyms are used in the field of percutaneous biopsies, as shown in Table  14.1. Biopsies in which needle positioning is guided by an imaging modality are called image-guided needle biopsies (IGNB). Over time, the techniques have evolved, and the names have changed. In the 1980s, the only needles available on the market were small needles (20G or less) intended for aspiration. Biopsies obtained using these needles were called fine-needle aspiration (FNA) or fine-needle aspiration cytology (FNAC), as the specimens consisted of cell suspensions that did not preserve tissue architecture. The diagnostic yield varied considerably across diseases, being fairly high for malignant epithelial tumors and much lower for lymphoproliferative disorders and infectious diseases. In the 1990s, cutting needles were developed. Cutting needles are larger in diameter than aspiration needles, between 20 and 14G, and are frequently used with a co-axial introducer to allow multiple passes and multiple sample harvesting through a single biopsy track. These needles are used with semi-automated or automated biopsy guns to harvest cores of tissue (core needle biopsy, CNB) that preserve tissue architecture and contain a far larger number

Table 14.1  Abbreviations Acronyms Legend TNB

Thoracic needle biopsy

IGNB

Image-guided needle biopsy

FNAB

Fine-needle aspiration biopsy

FNAC

Fine-needle aspiration cytology

PNAB

Percutaneous needle aspiration biopsy

CNB

Core needle biopsy

of cells than do aspiration samples. At the chest, percutaneous biopsies performed using fine-needle aspiration are called transthoracic needle aspiration biopsies (TTNAB or TNAB), and those performed using cutting needles are known as transthoracic needle biopsies (TNB). When comparing results published in the literature, the reader must be aware of these subtle differences, which may account in part for the discrepancies in diagnostic yields and complication rates. Indeed, the needle diameter and the number of passes probably play an important role in both, as discussed later. As indicated above, the term percutaneous transthoracic needle biopsy refers to core needle biopsy in this chapter.

14.3 Techniques 14.3.1 Preoperative Investigations 14.3.1.1  Coagulation Indices Guidelines about routine clotting studies before performing percutaneous lung biopsy recommend that the platelet count, prothrombin time (PT), and activated partial thromboplastin time (APTT) be checked [9]. Opinion in the world literature suggests that a PT reported as the international normalized ratio (INR) or an APTT ratio greater than 1.4, or a platelet count below 100,000/mL may be relative contraindications to percutaneous lung biopsy (Fig.  14.1) [10]. Oral anticoagulation should be stopped before the procedure, and, depending on the risk of thrombosis associated with the condition warranting anticoagulant therapy, the INR can be measured and, if necessary, heparin instituted once the INR falls below the therapeutic range. There is no evidence to support withholding antiplatelet drugs before the procedure.

14.3.1.2 Pulmonary Function The FEV1 cutoff below which percutaneous transthoracic needle biopsy lung biopsy is contraindicated has not been specified. Most practicing physicians and radiologists use a FEV1 cutoff of 1 L.

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Fig. 14.1  CT-guided lung biopsy in a patient treated by allogeneic BMT for acute lymphoblastic leukemia and thought to have invasive lung aspergillosis. The platelet count remained below 30,000/mm3 despite platelet transfusion. Mild alveolar hemor-

rhage (asterisk) occurred during the procedure but required no specific treatment. The biopsy confirmed the diagnosis of invasive pulmonary aspergillosis

14.3.1.3 Computed Tomography (CT)

biopsy is appropriate and must be available to the radiologist at the time of the biopsy. Repeat imaging should be performed if there has been a substantial change in the patient’s clinical condition or a long time between the last imaging studies and the biopsy. Finally, the localizing CT scan done at the time of the biopsy may show major changes that may affect the decision to perform a biopsy, the target, or the expected needle trajectory.

Obtaining a CT scan before any further intervention in patients believed to have lung disease has several advantages. Performing CT before fiberoptic bronchoscopy (FOB) has been shown to increase the diagnostic yield of FOB by directing the bronchoscopist to the site most likely to give a diagnosis. CT can also show peripheral masses not visible by bronchoscopy and may suggest that histological specimens would be best obtained using other methods, such as percutaneous biopsy. On the contrary, diffuse consolidation or ground-glass opacities may be better investigated by noninvasive tests or bronchoalveolar lavage (BAL) than by percutaneous biopsy. CT scans and all previous radiological investigations should be carefully reviewed to decide whether a

14.3.2 Biopsy Lung biopsies are usually performed under CT guidance. Ultrasound guidance may be used when the mass

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is in contact with the chest wall. When the lesion is deep, however, the ultrasound beam is scattered as it passes through the aerated lung. Conversely, ultrasound is particularly useful for large apical lesions, which can be better approached from the supraclavicular area (Fig. 14.2). The method used for imaging guidance is selected by the interventional radiologist based on a careful review of the pre-biopsy CT scan. For CT-guided procedures, patients are positioned prone, supine, or in lateral decubitus to ensure easy and safe access to the target lesion. Then, a short spiral CT acquisition of the region of interest is obtained. Because anatomical landmarks change substantially with patient position, this new set of images obtained in the biopsy position is used to determine the entry site of the needle on the patient’s skin and to plan the most direct and safest

needle trajectory. The needle must avoid lung fissures, bullae, large airways, and large vessels (Fig. 14.3). To minimize the risk of pneumothorax, the needle tip must be kept at a distance from the pleuropulmonary interface (Figs. 14.3 and 14.4). Care should be taken to avoid the internal mammary vessels if the biopsy is performed via an anterior approach. For ultrasoundguided procedures, the patient is placed in the supine, lateral, or prone position. The trajectory to the pulmonary lesion is determined and the entry site marked on the skin. Percutaneous transthoracic needle biopsy of the lung should be performed using standard universal precautions. Protective gloves should be worn. The entry site is cleaned and sterilely draped, and a 1% lidocaine solution is administered for local anesthesia. A co-axial technique should be used for both CT and ultrasound

Fig. 14.2  Ultrasound-guided biopsy in a 65-year-old patient with lymphoma. Ultrasonography allowed real-time control of needle progression near the right subclavian vessel (in red with color

Doppler, image c) and right carotid (arrows, images a and c). Image b shows pleural extension of the lymphoma

14  The Increasing Role for Core Needle Biopsy of Pulmonary Lesions in Immunocompromised Patients

guidance to allow multiple passes and to minimize the number of pleural punctures [10, 11]. With ultrasound guidance, needle progression is monitored in real time. With CT, axial 3- to 6-mm-thick slices are acquired to

Fig.  14.3  Simulation of CT-guided lung biopsy. Keeping the needle in the peripheral lung parenchyma avoids injury of the large vessels. When proximal biopsies are needed (pulmonary hilum), the needle trajectory should be parallel to the vessels to avoid injury

Fig. 14.4  CT-guided lung biopsy. The needle trajectory should avoid the lung fissures, and the needle tip should be kept as far as possible from the pleuropulmonary interface to minimize the risk of pneumothorax. Here, the patient was first placed in the

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monitor the needle progression toward the target. When appropriate positioning of the co-axial introducer is confirmed, a semi-automatic 18- to 20-G cutting needle is inserted. Collected samples are conditioned according to the clinical requirements (Fig. 14.5). This technique is supported by several recent studies indicating that the use of 18- or 20-G cutting needles, as well as co-axial techniques, improve the diagnostic yield and achieve diagnostic accuracies of 74–95% for malignancies [12–14]. False-negative results for malignancies may be due to a variety of factors including the patient’s inability to cooperate, small lesion size, overlying bone partly or completely masking the lesion, and sampling of necrotic tissue or pneumonitis distal to an obstructing lesion [15, 16]. The false-negative rate has been shown to be significantly lower with cutting needles than with aspiration [17]. No data are available on the immediate assessment of core adequacy, and visual inspection to confirm that the sample is adequate seems reasonable. However, touch preparations (imprints) of core biopsy specimens used to allow a rapid cytological evaluation may be as accurate as conventional cytopathological methods [18].

prone position (a). However, the major fissure (arrows) was along the planned needle trajectory. The patient was placed in the supine position, which allowed safe performance of the biopsy (b)

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a

b

c

d

e

f

Fig. 14.5  CT-guided lung biopsy in a patient with chronic lymphoid leukemia who developed small lung nodules. The procedure started with a short CT acquisition used to localize the lesion and to plan the needle trajectory. Radioopaque markers were placed on the skin to indicate the entry site (arrow on (a)).

Successive axial slices (b–d) were acquired to monitor needle progression toward the target. After the biopsy, alveolar hemorrhage developed (e and f). This unexpected minor complication plugs the needle track and prevents pneumothorax

After the lung biopsy, patients should be monitored for 4–6 h for delayed side effects such as pneumothorax. Simple clinical monitoring ensures the early detection of complications during the time needed for clotting of the needle track to occur.

method and to determine the priorities should the amount of biopsy material be limited. Optimal conditioning is crucial to obtain a high diagnostic yield. In all patients, at least one core biopsy should be fixed in a solution of acetic acid, formaldehyde, and alcohol (AFA solution). AFA solution fixation was selected based on its ability to allow high-quality structural analysis and its satisfactory performance in preliminary immunohistochemistry (IHC) studies. Although the AFA solution preserves the membrane and cytoplasmic epitopes and allows a number of molecular biology studies, nuclear antigens are not well preserved. Formaldehyde solutions allow the full range of immunohistochemical studies but

14.3.3 Sample Conditioning The referring clinician, pathologist, microbiologist, and interventional radiologist should work together. In particular, the referring clinician should discuss the suspected diagnoses with the interventional radiologist to assist in selecting the sample conditioning

14  The Increasing Role for Core Needle Biopsy of Pulmonary Lesions in Immunocompromised Patients Table 14.2  Different staining available on lung specimens Stain Utility Hematoxylin and eosin

Basic structural diagnosis

Reticulin

Fibers (sarcoma, fibrosis)

PAS (periodic acid Schiff)

Pathogens

MGG (May-GrünwaldGiemsa)

Basophilic cytoplasmic proteins Pathogens (Pneumocystis)

Ziehl

Acid-fast bacilli

GMS (Grocott methenamine silver)

Fungi

are not used as they produce inferior-quality structural data. After fixation, the samples are embedded in paraffin, sliced, and stained according to the underlying disease and suspected diagnoses (Table  14.2). IHC uses monoclonal antibodies to target specific antigens. These antibodies are then targeted by a secondary antibody that is later marked with the staining agent. IHC provides additional structural information, thus benefiting the diagnosis, and may help to select targeted treatments (e.g., rituximab to target CD20+ cells). Whenever possible, one of the cores should be frozen in liquid nitrogen as soon as possible after the biopsy. Frozen samples are highly versatile. They can be used for further structural analysis when the fixed specimens are not contributive, with good results. In addition, bacteria, fungi, and viruses can be reactivated. Last, preservation in frozen samples of intact proteins and nuclear material allows cytogenetic and molecular biology tests. Samples from severely immunocompromised patients should be placed in a sterile tube with saline for ancillary studies to detect pathogens. Structural studies can provide information on pathogens (fungi and acid-fast bacilli). When needed, this information can be acquired from fresh samples. Fresh samples require rapid conditioning and processing but allow extensive investigations for fungi, bacteria, and viruses by microscopic examination and culture. Viral infections can be detected using molecular biology tests on either fresh samples or cell culture extracts, and the results should be compared to serum viral load.

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14.3.4 Safety, Major and Minor Complications Operators should routinely audit their own practice and calculate their complication rates to inform their patients before asking them to consent to the procedure. They should strive to achieve rates at the lower end of the reported range. In an international survey, major complications included pneumothorax (20.5% of biopsies), pneumothorax requiring a chest drain (3.1%), hemoptysis (5.3%), and death (0.15%) [19].

14.3.4.1 Serious Complications Serious complications requiring specific treatment are rare. They include pneumothorax requiring drainage, hemopericardium (Fig.  14.6), hemothorax, hemoptysis, and severe pain [2, 12, 20–24]. The rates of the main complications are reported in Table 14.3.

Pneumothorax Chest tube placement is required for post-procedural pneumothorax in 3–15% of all lung biopsies [25]. Most patients with pneumothorax necessitating chest tube drainage have lesions located less than 2 cm from the pleural membrane [26]. The tube can usually be removed within 48 h. In patients with severe pulmonary destruction, due for instance to emphysema or graft-versus-host disease, the chest tube may need to be left in place for several days because of the decreased pulmonary compliance (Fig. 14.7).

Bleeding Intrapulmonary hemorrhage occurs during lung biopsy in 5–30% of patients and hemoptysis in 1.25–5% [19, 27]. Lesion depth has been identified as the most important risk factor for hemorrhage, with an increased risk of bleeding in lesions deeper than 2 cm [28]. The hemothorax rate is about 1.5%. Clinically significant hemorrhage is rare. Hemothorax may result from injury to an intercostal or internal thoracic artery (Fig. 14.8) or vein [29].

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Fig.  14.6  CT-guided biopsy in an uncooperative 73-year-old patient. The patient moved during the procedure despite having previously received explanations on the risks of moving. A con-

trol image showed the needle in the pericardial sac, and a pericardial effusion developed rapidly (arrows, image d). Pericardial drainage was successful

Table 14.3  Major side effects reported after CT-controlled pulmonary biopsies in the literature Risk No. of procedures Needle Pneumothorax (total/ chest tube)

Bleeding (total/hemoptysis)

Vasovagal response

References

23/5%

660

19G CNB

[31]

62/31%

61

18G PNAB

[39]

28/2.5%

162

22G PNAB

[47]

26/8%

846

19G PNAB

[30]

21/2%

97

19G PNAB

[6]

17/2%

135

17G CNB

[26]

17/0.5%

605

19G CNB

[64]

30/4%

660

19G CNB

[31]

–/2%

846

19G PNAB

[30]

27/6%

135

17G CNB

[26]

20/3.8%

604

19G CNB

[64]

0.3%

846

19G PNAB

[30]

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Fig. 14.7  CT-guided lung biopsy in a 55-year-old patient after allogeneic bone marrow transplantation for lymphoma. The target lesion is located less than 2  cm from the thoracic wall. Despite careful needle placement, a large pneumothorax

occurred and failed to resolve with aspiration, necessitating chest tube placement. The biopsy demonstrated organizing pneumonia due to graft-versus-host disease

Pain

14.3.4.2 Minor Complications

Pain is a rare complication (0.3% of the patients) that may occur in the absence of a specific injury, despite careful local anesthesia. Pain may be accompanied by vasovagal syncope, a drop in arterial oxygen saturation, or hypotension. These manifestations usually resolve spontaneously. However, acute pain during lung biopsy mandates close monitoring of the patient for evidence of a serious complication. After the procedure, patients are in general monitored in the emergency room for a few hours, after which they are discharged if no adverse events have occurred (Fig. 14.9).

Minor complications occur in 30–60% of lung biopsies. Among these asymptomatic biopsy-related events, the most common are small pneumothorax (17–60%) and alveolar hemorrhage (5–30%) [26]. Usually, these asymptomatic complications resolve spontaneously and require no treatment after the biopsy (Fig.  14.10). The rate of pneumothorax/ bleeding is highest with lesions smaller than 2 cm (tenfold higher risk of pneumothorax and sixfold higher risk of bleeding). The risk of pneumothorax is seven times higher when the lesion is less than 2  cm from the chest wall (Fig.  14.10). However,

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Fig. 14.8  CT-guided lung biopsy in an 18-year-old patient with suspected relapsing Hodgkin’s disease. Care was taken to stay close to the manubrium (image b) to avoid the internal thoracic

artery (arrow, image a). However, after three biopsies the artery was injured and severe hemothorax developed (asterisk, image d). Treatment was successful

CT-guided biopsy of lesions more than 2 cm from the chest wall is associated with a tenfold increase in the bleeding rate [31]. Longer length of the intrapulmonary needle track (>4 cm) is also associated with higher rates of bleeding around the track and of pneumothorax [26]. Bleeding and pneumothorax are more common when the pleural membrane is crossed twice by the needle. The risk of pneumothorax is also higher in patients with bullae and in those receiving mechanical ventilation. An oblique trajectory of the needle relative to the pleural membrane may increase the risk of pneumothorax [31]. Decreasing the duration of the procedure diminishes the pneumothorax rate [26]. The use of smaller co-axial introducers (19 G instead of 17 G) substantially decreases the risk of

pneumothorax without affecting diagnostic accuracy, sensitivity, or specificity of the histopathologic diagnosis of pulmonary nodules [30]. Although pneumothorax rates are similar with FNAB and automated core biopsy, the automated devices are associated with a small and nonsignificant increase in the rate of bleeding with hemoptysis [12, 32]. However, no statistically significant relationship has been found between complication rates, number of passes through the co-axial system with the introducer needle or core gun (up to 4), and smoking history. The complication rate seems similar for masses, consolidations, and ground-glass opacities [33]. In our experience, the number of biopsy-related complications is not different between immunocompromised and immunocompetent patients.

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Fig. 14.9  CT-guided lung biopsy in a 65-year-old patient with organizing pneumonia. The patient experienced severe pain at the end of the procedure with a vasovagal syncope. The control

image shows alveolar hemorrhage, but no hemoptysis occurred. The patient was monitored in the emergency room for 6 h then discharged

Monitoring

complete information before they are discharged so that they can be alert to symptoms possibly indicating the development of a complication.

Most complications occur immediately or within the first hour of the transcutaneous lung biopsy. A limited number of CT slices are acquired at the end of the procedure to detect early complications. Pneumothorax is usually detectable by chest X-ray 1 h after the biopsy [22, 34–36], although recent reports describe delayed pneumothorax occurring 24 h after the biopsy despite normal chest X-rays 1 and 4  h post-biopsy [37]. No specific monitoring is required following an uncomplicated biopsy procedure, but patients should remain hospitalized for at least 1 h, or longer if further radiographs are required to monitor a pneumothorax. Patients should be in a supervised area so staff can be alerted if they develop shortness of breath, chest pain, or other symptoms. Last, they should be given

14.4 Efficiency 14.4.1 Sensitivity and Adequacy The number of lung biopsies has increased considerably over the last decade. As fine-needle aspiration gained in popularity, its accuracy came under scrutiny. Audits showed that fine-needle biopsy was more likely to detect malignant disease than were any of the noninvasive tests or endoscopic bronchial sampling [38].

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Fig. 14.10  CT-guided lung biopsy in a 32-year-old patient after stem cell transplantation for acute leukemia. The target lesion is located less than 10 mm from the chest wall. A small and stable

pneumothorax developed during the procedure. No specific treatment was required. The small pneumothorax was not visible by chest X-ray. The biopsy showed organizing pneumonia

Several large studies of the efficiency of percutaneous transthoracic needle biopsy have been reported. Greater than 80% sensitivity and accuracy can be achieved (Table 14.4) [39]. The false-positive rate is usually less than 1% [40, 41] and the false-negative rate less than 5–10% [42–45]. Diagnostic accuracy depends on the size and location of the lesion, operator experience, needle type, needle path length, biopsy technique, and expertise of the cytopathologist [10, 46, 47]. Larger lesions are more likely to enable a positive diagnosis of malignancy [10, 48–52], although some operators have reported no significant difference between lesions smaller than 2 cm and lesions ³2 cm in diameter [53, 54]. With CT-guided percutaneous transthoracic needle biopsy, accuracy is 91% and sensitivity 94% for large

nodules (>15 mm) compared to 88% and 82%, respectively, for small nodules (<10 mm) (Fig. 14.11) [39]. Diagnostic accuracy for needle path lengths of 40 mm or less is significantly greater (>90%) than that for lengths greater than 40 mm (<56%). The overall diagnostic accuracy is 96% for procedures performed with 18-G needles and 92% for procedures performed with 19-G needles, with 95% and 89% sensitivity and 100% and 99% specificity, respectively [30]. Whether lung biopsy should be considered for persistent focal ground-glass opacities remains unclear. However, in a 2009 study of 28 patients with ground-glass opacities, 17 with malignant and 11 with benign lesions, percutaneous transthoracic needle biopsy had 71% overall sensitivity and 82% accuracy [33].

14  The Increasing Role for Core Needle Biopsy of Pulmonary Lesions in Immunocompromised Patients Table 14.4  Effectiveness of the biopsy according to the type of pulmonary lesions Sensitivity (%) Accuracy (%) No. of procedures

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References

Overall

82 87 91

88 77 94

61 162 846

[39] [47] [30]

Malignancy   <10 mm   <10 mm   <15 mm   >15 mm   >20 mm

89 88 67 72 94 75

91 92 80 74 96 88

604 47 10 70 27 8

[64] [39] [33] [6] [6] [33]

Infection fungal

70.6

76.4

17

[57]

Fig. 14.11  CT-guided biopsy in a patient treated for MALT lymphoma. The biopsy of the 8-mm nodule located in the lower right lobe showed a metastasis from an unsuspected melanoma

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In our experience, the diagnostic yield is higher for masses and nodules than for consolidations or diffuse infiltrates. Agreement between biopsy results and the final diagnosis is generally good (kappa, 0.80; P < 0.0001). Eighty percent of percutaneous lung biopsies harvest a sufficient amount of tissue for the pathologic diagnosis [55].

14.4.2 Specific Diagnoses In patients with lung infections, lung biopsy has been reported to have 70% sensitivity and 100% positive predictive value [56, 57]. Lung biopsy performs better for diagnosing bacterial infections (Fig. 14.12) (100% sensitivity) than fungal infections (Fig.  14.13) (30–70% sensitivity). The diagnosis of invasive fungal infection is

C. de Bazelaire et al.

rarely achieved by commonly used diagnostic procedures such as CT, sputum examination, BAL, fungal cultures, and antigen detection. BAL is usually performed in neutropenic patients if the imaging features suggest a fungal infection, but is only 50% sensitive for aspergillosis [58–60]. Bronchoscopy and BAL may fail to differentiate colonization from invasive infection. Transbronchial biopsy, performed only when the platelet count is >50·109/L, improves diagnostic accuracy by only 6.5% [58]. Histology is more effective than culturing for the diagnosis of bacterial and fungal infections. Cultures are usually positive in fewer than 40% of patients with aspergillosis or mucormycosis [57]. Cultures are often negative in neutropenic patients and in patients given empirical antifungal or antibacterial agents before sampling [61]. Fungal and bacterial cultures may produce false-negative results. For instance, Aspergillus is a common saprophyte, and a positive

Fig. 14.12  CT-guided lung biopsy in a 64-year-old patient with a long history of chronic lymphoid leukemia and a new lung mass, suggesting aggressive lymphomatous transformation. The biopsy showed tuberculosis

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Fig. 14.13  CT-guided lung biopsy in a patient treated for B-cell lymphoma. The planned needle trajectory passed through a pleural tail to avoid the lung parenchyma. The biopsy demonstrated invasive pulmonary aspergillosis

culture is therefore not proof of infection. Hence, the gold standard is mycological and/or histological evidence of tissue invasion. Biopsy allows differentiation between aspergillosis and mucormycosis, which is important, as Mucorales are usually resistant to azoles and echinocandins and consequently require amphotericin B for curative treatment and secondary prophylaxis during bone marrow transplantation. Also, histology provides the diagnosis immediately. Histological studies show necrotic foci containing numerous filamentous fungi in patients with fungal infection and granulomas and infiltrates composed of histiocytes or neutrophils in those with bacterial infection. Image-guided percutaneous transthoracic fine-needle aspiration biopsy (FNAB) has proved reliable for differentiating benign and malignant pulmonary lesions. Diagnostic accuracy exceeded 93% [49, 62] and sensitivity exceeded 95% [12, 54, 62]. For nodules <10 mm, overall sensitivity was 68% and accuracy was

78% [63], compared to 93% and 95%, respectively, for nodules <15 mm [53]. In a study of 605 biopsies, lesion size £10 mm was associated with a tenfold increase in the false-negative rate [64]. The positive and negative predictive values of 100% and 60–81%, respectively, have been reported [30, 63]. In patients with lymphoma, lung biopsy establishes the diagnosis in up to 90% of cases. In false-negative cases, histology may show inflammatory changes and necrosis. De novo non-hematological malignancies involving the lung are diagnosed by lung biopsy in 90% of cases [30]. Lung biopsy may assist in the diagnosis of organizing pneumonia, graft-versus-host disease with pulmonary complications, and benign tumors. Figures 14.14 and 14.15 show the diagnostic yield of lung biopsy in patients with non-infectious conditions. Figure 14.16 describes a case of pulmonary nocardiosis in a patient with chronic lymphocytic leukemia who was thought to have aggressive lymphoma.

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Fig. 14.14  CT-guided lung biopsy in a 63-year-old patient with a history of non-Hodgkin’s lymphoma and a suspected pulmonary relapse. The biopsy unexpectedly showed an adenocarcinoma

Fig. 14.15  CT-guided lung biopsy in an 83-year-old patient with a history of non-Hodgkin’s lymphoma and a suspected pulmonary relapse. The biopsy confirmed the relapse

14  The Increasing Role for Core Needle Biopsy of Pulmonary Lesions in Immunocompromised Patients

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Fig. 14.15  (continued)

Fig. 14.16  CT-guided lung biopsy in a patient with chronic lymphocytic leukemia who was thought to have aggressive lymphoma. The biopsy diagnosis was pulmonary nocardiosis

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14.5 Conclusion CT-guided transthoracic lung biopsy is highly ­accurate for diagnosing malignancies and valuable for detecting infections in immunocompromised patients, provided the processing and routing of the biopsy samples are optimal. This technique is generally safe, the main complications being pneumothorax and hemorrhage. Both complications are associated with variables such as lesion size, lesion depth, number of pleural needle passes, and procedure duration. Most complications are minor and easily managed in the CT room. In-depth knowledge of predisposing factors allows clinicians and radiologists to anticipate complications and to ensure that the patient receives optimal monitoring after the procedure.

References   1. Haaga JR, Alfidi RJ (1976) Precise biopsy localization by computer tomography. Radiology 118:603–607   2. Westcott JL (1988) Percutaneous transthoracic needle biopsy. Radiology 169:593–601   3. van Sonnenberg E, Lin AS, Deutsch AL, Mattrey RF (1983) Percutaneous biopsy of difficult mediastinal, hilar, and pulmonary lesions by computed tomographic guidance and a modified coaxial technique. Radiology 148:300–302   4. Stanley JH, Fish GD, Andriole JG et al (1987) Lung lesions: cytologic diagnosis by fine-needle biopsy. Radiology 162: 389–391   5. Khouri NF, Stitik FP, Erozan YS et al (1985) Transthoracic needle aspiration biopsy of benign and malignant lung lesions. Am J Roentgenol 144:281–288   6. Li H, Boiselle PM, Shepard JO, Trotman-Dickenson B, McLoud TC (1996) Diagnostic accuracy and safety of CT-guided percutaneous needle aspiration biopsy of the lung: comparison of small and large pulmonary nodules. Am J Roentgenol 167:105–109   7. Larscheid RC, Thorpe PE, Scott WJ (1998) Percutaneous transthoracic needle aspiration biopsy: a comprehensive review of its current role in the diagnosis and treatment of lung tumors. Chest 114:704–709   8. Tsukada H, Satou T, Iwashima A, Souma T (2000) Diagnostic accuracy of CT-guided automated needle biopsy of lung nodules. Am J Roentgenol 175:239–243   9. British Thoracic Society guidelines on diagnostic flexible bronchoscopy. Thorax 2001 56(1):1–21 10. Moore EH (1998) Technical aspects of needle aspiration lung biopsy: a personal perspective. Radiology 208: 303–318 11. Yankelevitz DF, Vazquez M, Henschke CI (2000) Special techniques in transthoracic needle biopsy of pulmonary nodules. Radiol Clin North Am 38:267–279 12. Klein JS, Salomon G, Stewart EA (1996) Transthoracic needle biopsy with a coaxially placed 20-gauge automated cutting needle: results in 122 patients. Radiology 198:715–720

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14  The Increasing Role for Core Needle Biopsy of Pulmonary Lesions in Immunocompromised Patients 30. Geraghty PR, Kee ST, McFarlane G, Razavi MK, Sze DY, Dake MD (2003) CT-guided transthoracic needle aspiration biopsy of pulmonary nodules: needle size and pneumothorax rate. Radiology 229:475–481 31. Yeow KM, Su IH, Pan KT et al (2004) Risk factors of pneumothorax and bleeding: multivariate analysis of 660 CT-guided coaxial cutting needle lung biopsies. Chest 126:748–754 32. Lucidarme O, Howarth N, Finet JF, Grenier PA (1998) Intrapulmonary lesions: percutaneous automated biopsy with a detachable, 18-gauge, coaxial cutting needle. Radio­ logy 207:759–765 33. Hur J, Lee HJ, Nam JE et al (2009) Diagnostic accuracy of CT fluoroscopy-guided needle aspiration biopsy of groundglass opacity pulmonary lesions. AJR Am J Roentgenol 192:629–634 34. Poe RH, Kallay MC (1987) Transthoracic needle biopsy of lung in nonhospitalized patients. Chest 92:676–678 35. Stevens GM, Jackman RJ (1984) Outpatient needle biopsy of the lung: its safety and utility. Radiology 151:301–304 36. Perlmutt LM, Braun SD, Newman GE, Oke EJ, Dunnick NR (1986) Timing of chest film follow-up after trans­ thoracic needle aspiration. AJR Am J Roentgenol 146: 1049–1050 37. Brown KT, Brody LA, Getrajdman GI, Napp TE (1997) Outpatient treatment of iatrogenic pneumothorax after needle biopsy. Radiology 205:249–252 38. Johnston WW (1988) Fine needle aspiration biopsy versus sputum and bronchial material in the diagnosis of lung cancer. A comparative study of 168 patients. Acta Cytol 32:641–646 39. Wallace MJ, Krishnamurthy S, Broemeling LD et al (2002) CT-guided percutaneous fine-needle aspiration biopsy of small (< or =1-cm) pulmonary lesions. Radiology 225: 823–828 40. Denley H, Singh N, Clelland CA (1997) Transthoracic fine needle aspiration cytology of lung for suspected malignancy: an audit of cytological findings with histopathological correlation. Cytopathology 8:223–229 41. Simpson RW, Johnson DA, Wold LE, Goellner JR (1988) Transthoracic needle aspiration biopsy. Review of 233 cases. Acta Cytol 32:101–104 42. Komiya T, Kusunoki Y, Kobayashi M et  al (1997) Transcutaneous needle biopsy of the lung. Acta Radiol 38: 821–825 43. Greif J, Marmor S, Schwarz Y, Staroselsky AN (1999) Percutaneous core needle biopsy vs. fine needle aspiration in diagnosing benign lung lesions. Acta Cytol 43:756–760 44. Bocking A, Klose KC, Kyll HJ, Hauptmann S (1995) Cytologic versus histologic evaluation of needle biopsy of the lung, hilum and mediastinum. Sensitivity, specificity and typing accuracy. Acta Cytol 39:463–471 45. DiBonito L, Colautti I, Patriarca S, Falconieri G, Barbazza R, Vielh P (1991) Cytological typing of primary lung cancer: study of 100 cases with autopsy confirmation. Diagn Cytopathol 7:7–10 46. Murphy JM, Gleeson FV, Flower CD (2001) Percutaneous needle biopsy of the lung and its impact on patient ­management. World J Surg 25:373–379, discussion 379–380 47. Ohno Y, Hatabu H, Takenaka D et al (2003) CT-guided transthoracic needle aspiration biopsy of small (< or = 20 mm)

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Minimally Invasive Diagnostic Strategy in Immunocompromised Patients with Pulmonary Infiltrates

15

Laurent Camous, Virginie Lemiale, Achille Kouatchet, David Schnell, Sandra de Miranda, and Élie Azoulay

Contents 15.1 Introduction............................................................. 175 15.2 The DIRECT Approach: A Guide for Selecting the Initial Antimicrobial Treatment and Investigations................................ 177 15.3 Bronchoscopy and Bronchoalveolar (FO-BAL) Lavage in Cancer Patients with Pulmonary Infiltrates..................................... 178 15.4 Diagnostic Strategy Without Bronchoscopy......... 178 15.4.1 Laboratory Tests for Diagnosing Infectious............. 179 15.5 Conclusion and Avenues for Future Research..... 185 References............................................................................ 185

L. Camous, V. Lemiale, A. Kouatchet, D. Schnell, and S. de Miranda Paris-7 Paris-Diderot University, UFR de Médecine, 1 avenue Claude Vellefaux, 75010 Paris, France É. Azoulay (*) and V. Lemiale Service de Réanimation Médicale, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010, Paris, France and Medical Intensive Care Units, Saint-Louis Hospital, Paris 7 University, Paris, France e-mail: [email protected]

15.1 Introduction Physicians in most medical specialties are seeing a growing number of patients with solid tumours and haematological malignancies. The implementation of routine screening policies has improved the early diagnosis of cancer, and treatment advances have been achieved, with the result that prolonged survival or complete recovery can be obtained in many patients. Intensive and prolonged treatment regimens introduced over the last decade have increased the overall survival rates among patients with various types of malignancies [1]. For instance, intensified and shortened cyclical chemotherapy for acute lymphoblastic leukaemia in adults has improved survival [2], advances in the understanding of multiple myeloma have led to the development of new drugs [3], targeted therapies have proved useful in patients with lymphoma and chronic myeloid leukaemia [4, 5], and growth factors that hasten neutropenia recovery have allowed higher-dose chemotherapy regimens that increase the chances for a cure [6]. However, treatment-related toxic and infectious complications have increased in lockstep with the expanding use of aggressive cancer treatments. Pulmonary events are the leading complications in patients treated for cancer. These events are frequently severe, with diffuse pulmonary infiltrates, hypoxaemia, and secondary dysfunction of other organs (i.e., shock and kidney injury) [7]. ARF is the most common reason for admission of cancer patients to the intensive care unit (ICU) [8–10]. In cancer patients admitted to the ICU for ARF, the mortality rate is about 50% overall, 60–70% when invasive mechanical ventilation is needed, and 80–90% in recipients of allogeneic bone marrow or

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_15, © Springer-Verlag Berlin Heidelberg 2011

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176 Table 15.1  Causes of pulmonary infiltrates in patients with solid tumors or hematological malignancies (Adapted from [16])

L. Camous et al.   Alveolar hemorrhage

Infections

  Transfusion-related acute lung injury

  Bacterial infections

  Radiation-induced lung damage

   Common pyogenic bacteria

  Alveolar proteinosis

    Streptococcus pneumoniae

  Diffuse alveolar damage

    Staphylococcus aureus

  Bronchiolitis

    Haemophilus influenzae

  Cryptogenic organized pneumonia

    Pseudomonas aeruginosa and Enterobacteriaceae

  Second malignancy

   Intracellular bacteria     Legionella pneumophila     Chlamydia and Mycoplasma pneumoniae    Other bacteria     Actinomyces israelii     Nocardia spp.   Pneumocystis jirovecii   Invasive fungal Infections    Molds     Aspergillosis    Emerging mycotic infection: trichosporosis, fusariosis, zygomycetes    Yeasts     Lung involvement during candidemia    Endemic fungal infections     Histoplasmosis, coccidioidomycosise, blastomycosis   Viral infections (primary infections or reactivations)    Seasonal respiratory viruses     Influenzae, parainfluenzae, rhinovirus     Respiratory syncytial virus    Herpes virus     Cytomegalovirus, herpes virus, zoster virus and HHV6    Other viruses: adenovirus   Mycobacterial infections    Tuberculosis and atypical mycobacteria Noninfectious causes   Cardiogenic pulmonary edema   Capillary leak syndrome   Lung infiltration   Drug-induced toxicity

stem cell transplants who require mechanical ventilation [11]. Non-invasive mechanical ventilation has improved survival in cancer patients requiring ventilation by reducing the need for endotracheal intubation [12–15]. A vast array of conditions can manifest as pulmonary infiltrates in patients with cancer (Table 15.1). Although the need for early treatment, most notably with antimicrobials, is universally recognized, debate continues about the best diagnostic strategy in cancer patients with pulmonary infiltrates [16]. Suggested diagnostic strategies cover an extensive spectrum ranging from empirical treatment without diagnostic investigations to diagnostic lung biopsy. However, most groups recommend diagnostic inve­ stigations. The main difference across strategies consists in whether fiberoptic bronchoscopy with bronchoalveolar lavage (FO-BAL) is performed (Table 15.2) [16]. The debate about the appropriateness of FO-BAL is particularly relevant in patients with hypoxemic ARF, among whom 40% experience respiratory status deterioration when FO-BAL is performed [17–19]. This risk must be weighed against the increased risk of death that is independently associated with failure to identify the cause of pulmonary infiltrates in patients with cancer [11, 20–22].  This review focuses on the diagnostic strategy for cancer patients with pulmonary infiltrates. We will start by briefly reviewing our DIRECT approach designed to increase the likelihood of appropriate antiinfectious therapy being given within 2 h after ICU admission (Fig. 15.1). We do not recommend a strategy based solely on the DIRECT approach, because identifying the cause of the pulmonary infiltrates increases the chances of survival. We describe the two

15  Minimally Invasive Diagnostic Strategy in Immunocompromised Patients with Pulmonary Infiltrates Table  15.2  The diagnostic strategy without bronchoscopy in cancer patients with pulmonary infiltrates (Adapted from [16]) Radiography   Chest radiography   Thin-section high-resolution computed tomography   Echocardiography or pleural ultrasonography Sputum   Bacteria   Tubercle bacillus   Fungi (aspergillus) Tests for Pneumocystis jirovecii (MGG staining and immuno-fluorescence) PCR for Pneumocystis jirovecii Blood cultures Serum tests   Serology: Chlamydia, Mycoplasma, Legionella   Herpes consensus PCR test   Circulating aspergillus antigen   Circulating cytomegalovirus antigen Nasopharyngeal aspiration   Tests for viruses (PCR and immunofluorescence) Urine tests   Cytology, bacteriology   Legionella antigen Biological markers   Brain natriuretic peptide (BNP) or ProBNP   Creactive protein   Fibrin   Procalcitonin

The DIRECT approach: a guide to select initial antimicrobial treatments and appropriate investigations Delay since malignancy onset or BMT Patterns of Immune deficiency Radiographic appearance Clinical Experience and Knowledge of the literature Clinical picture Findings by the high resolution computed Tomodensitometry (HRCT)

Fig. 15.1  The DIRECT approach for selecting the initial antimicrobial treatment (Adapted from [16]). This approach does not obviate the need for diagnostic investigations

main strategies for identifying the cause of pulmonary infiltrates, i.e., with and without FO-BAL. Because the diagnostic efficiency of FO-BAL was evaluated recently [16], we will focus on the strategy that does not include FO-BAL. In our ICU experience, although FO-BAL combined with other investigations fails to identify the cause of ARF in 10–15% of patients [11,

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23], severe hypoxemia and associated organ dysfunctions limit the feasibility of lung biopsy in many cases. However, studies have found lung biopsy to be highly efficient, and we raise this point in the last section of this review, which identifies areas for future research that may help us to improve the management of these very vulnerable patients.

15.2 The DIRECT Approach: A Guide for Selecting the Initial Antimicrobial Treatment and Investigations We recently proposed a clinical approach designed to help clinicians make hypotheses about the cause of pulmonary infiltrates in patients with haematological malignancies or solid tumours (Fig.  15.1) [16]. This empiric approach is being evaluated prospectively. In the next paragraphs, we describe this strategy and provide one or two examples for each situation. The main goal of the DIRECT approach is to target diagnostic and therapeutic efforts toward those conditions that are most likely to be present in the individual patient, instead of running through the entire list of causes of pulmonary infiltrates in cancer patients. By identifying the two or three diagnoses that are plausible in a given patient, the DIRECT approach may help to initiate appropriate treatment within a few hours after admission. D stands for Delay and refers to three time intervals that should be taken into account: (1) time from the diagnosis of malignancy, (2) time from respiratory symptom onset and (3) where relevant, time from allogeneic bone marrow transplantation (BMT). For example, pulmonary leukaemic infiltration or leukostasis occurs in patients with high counts of circulating blast cells, i.e., at the earliest stage of acute leukaemia or during relapses [24]. Gradually worsening dyspnea over the last 4 weeks is more likely to indicate pulmonary infiltration by the malignancy or congestive heart failure and pulmonary oedema than bacterial infection or Pneumocystis pneumonia (PCP). In allogeneic BMT recipients, cytomegalovirus pneumonia may occur during graft-versus-host disease (GVHD) but is unlikely to explain pulmonary infiltrates during the first 30 days after transplantation [25]. I indicates the type of Immune deficiency. This point is crucial when making hypotheses about the

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type of infection responsible for pulmonary infiltrates. Patients with lymphocyte abnormalities (e.g., acute or chronic lymphocytic leukaemia or lymphoma) are at risk for viral or fungal infections [e.g., herpes simplex virus (HSV), PCP, and emerging fungal infections], diseases affecting monocytes and macrophages (e.g., hairy cell leukaemia, chronic myelomonocytic leukaemia, and chronic myeloid leukaemia) are associated with intracellular bacterial infections (e.g., Legionella, Mycoplasma, and tuberculosis), and neutrophil abnormalities (e.g., absolute or relative neutropenia, myelodysplastic syndrome, and chronic myeloid leukaemia) increase the risk for bacterial and fungal infections. In addition, hypogammaglobulinaemia in patients with chronic lymphocytic leukaemia or myeloma is specifically associated with infection by encapsulated bacteria. However, all these patterns need to be re-evaluated using new technologies to assess the cellular defects. In addition, the increasing use of intensive and prolonged cancer chemotherapy regimens and of targeted therapies (e.g., rituximab and alemtuzumab) can be expected to change the patterns of immune deficiency seen in cancer patients and, therefore, qualitative studies are needed. R indicates the chest Radiograph findings. E refers to Experience and knowledge of the literature. For example, although diffuse alveolar haemorrhage can theoretically cause pulmonary infiltrates in immunosuppressed patients, this complication seems virtually confined to BMT recipients [26, 27]. Similarly, pulmonary aspergillosis, although possible in every cancer patient, occurs chiefly in patients with prolonged neutropenia (e.g., acute leukaemia patients), long-term steroid therapy [28, 29], and BMT [30]. T refers to findings by high-resolution computed Tomography (HRCT).

L. Camous et al.

particularly helpful in patients at very high risk of death if treated with mechanical ventilation [37]. The results of 18 studies (in 1,537 patients) indicated that FO-BAL provided the diagnosis in about half the patients and led to treatment modifications in one-third (Table 15.3). These data were confirmed by a recent retrospective study [38], including 175 haematological patients admitted to the ICU for ARF and showing a 10% rate of life-threatening complications after FO-BAL. Moreover, the diagnostic yield was only 50%, and the therapeutic impact was ­significant in only 17% of the patients [38]. Data from 764 BMT recipients in 15 studies showed that FO-BAL supplied the diagnosis in 55% of cases, but caused the respiratory status to deteriorate in up to 40% (Table 15.4) [17–19]. The limited diagnostic efficiency of FO-BAL in immunocompromised patients may be related to several factors. First, most patients are already on antimicrobial therapy at the time of FO-BAL. Therefore, bacterial pneumonia is usually documented clinically but not bacteriologically, although FO-BAL may detect resistant pathogens that require adjustment of the antimicrobial regimen. Second, BAL fluid analysis is often confined to tests for infections, and most studies fail to report the appearance of the alveolar cells, which may suggest drug toxicity, or the presence of malignant cells, indicating pulmonary infiltration. Third, most studies were conducted in the 1990s, before the introduction of new tools for diagnosing infections with viruses, parasites, and fungi [39]. However, the diagnostic yield of FO-BAL was not better in recent studies [11, 40]. Last, FO-BAL may be less efficient in patients with cancer than in those with AIDS because of pathophysiological differences in the development of pulmonary invasion by Aspergillus or Pneumocystis [30, 41–45]. For instance, a study of PCP in cancer patients showed marked inflammation and scarce Pneumocystis bodies, indicating that negative BAL fluid findings did not rule out PCP [43].

15.3 Bronchoscopy and Bronchoalveolar (FO-BAL) Lavage in Cancer Patients with Pulmonary Infiltrates 15.4 Diagnostic Strategy Without Bronchoscopy In the late 1980s, FO-BAL became the most widely used investigation for identifying the cause of pulmonary infiltrates in immunosuppressed patients [31–36]. FO-BAL superseded lung biopsy, as it was easier, simpler, and less invasive. These advantages were reported to be

Table 15.2 lists the investigations used in the diagnostic strategy without FO-BAL. Routinely performing all these tests may be an alternative to FO-BAL in most

15  Minimally Invasive Diagnostic Strategy in Immunocompromised Patients with Pulmonary Infiltrates

179

Table 15.3  Studies of fiberoptic bronchoscopy with bronchoalveolar lavage in patients with malignancies and pulmonary infiltrates (Adapted from [16]) Reference Diagnosis Diagnostic impact Therapeutic impact n Stover et al. [96]

97

HM

66

–

Martin et al. [109]

100

HM

30

–

Xaubet et al. [110]

96

HM

49

31

Campbell et al. [111]

22

HM

55

–

Pisani et al. [112]

150

HM

39

–

Maschmeyer et al. [113]

46

Neutropenia

30

–

Cordonnier et al. [100]

56

Neutropenia

53

24

Cazzadori et al. [114]

142

HM

36

–

Von Eiff et al. [40]

90

HM

66

65

White et al. [3]

68

HM

31

24

Ewig et al. [28]

49

HM

31

16

Gruson et al. [18]

41

Neutropenia

63

28

Hilbert et al. [22]

24/46

HM

62

71

Murray et al. [2]

27

HM

33

28

Azoulay et al. [4]

203

HM

49.5

45.1

Pagano et al. [115]

127

HM

53

14

Jain et al. [82]

104

HM

56

–

Hohenadel et al. [81]

95

HM

30

–

Total

1537

46.2

34.6

cancer patients with pulmonary infiltrates (Fig. 15.2 and 15.3). We review available data on the use of each of these investigations in cancer patients. Imaging findings are discussed in another chapter 12. We will focus on laboratory methods to diagnose pulmonary infiltrates.

identified organisms may indicate colonisation rather than infection. In a population of allogeneic BMT recipients, no pathogen was isolated in 70% of the patients, and some of the isolated microorganisms (such as Candida spp., coagulase-negative staphylococci, and enterococci) were probably mere contaminants [46]. As shown by studies of FO-BAL, conventional microbiological testing may fail to identify the cause 15.4.1 Laboratory Tests of lower respiratory tract infection. In patients on for Diagnosing Infectious broad-spectrum antibiotics at the time of sample collection, gram staining and culturing have low sensitiv15.4.1.1 Bacterial Infections ity, and cultures require time. Furthermore, these methods fail to distinguish colonisation from infecBacterial pneumonia in immunocompromised patients tion. Serological testing is slow and often lacks both is usually due to gram-negative bacilli or Staphylococcus sensitivity and specificity. In most cases, the causative aureus. Selection pressure due to the use of broad-­ pathogen is not found, despite optimal investigations. spectrum antibiotics explains the emergence of resistant Methods that rapidly identify the causative pathogen gram-negative strains. As discussed above, FO-BAL would help physicians to select the best treatment often fails to establish the exact diagnosis. Moreover, strategy. Such methods are already available for

180

L. Camous et al.

Table 15.4  Studies of fiberoptic bronchoscopy with bronchoalveolar lavage in bone marrow transplant recipients with pulmonary infiltrates (Adapted from [16]) Author Type of Diagnostic Therapeutic Complications n patients impact impact Springmeyer et al. [20]

22

Auto-allo

58

–

13

Corodonnier et al. [17]

52

Allo

50

–

0

Cordonnier et al. [9]

69

Allo

66

–

–

Milburn et al. [19]

40

Allo

80

76

0

Springmeyer [78]

15

Auto-allo

89

–

40

Heurlin et al. [116]

18

Auto-allo

61

–

–

Weiss et al. [80]

47

Auto-allo

47

–

12

Campbell et al. [79]

27

–

74

63

11

AbuFarsakh et al. [117]

77

Auto-allo

42

–

–

White et al. [93]

68

Auto-allo

31

24

15 (7% MV)

Dunagan et al. [1]

71

Auto-allo

38

42

27 (4% MV)

Glazer et al. [118]

79

Auto-allo

67

62

–

Gruson et al. [39]

38

Auto-allo

42

–

–

Gruson et al. [18]

52

Auto-allo

38

28

17

Huaringa et al. [108]

89

Auto-allo

42

–

–

Total

764

Auto-allo

55

49

0–40%

a

32% Mechanical ventilation

a

Pulmonary infiltrates in cancer patients

(neutropenic, BMT-recipients, chemotherapy, other immunosuppressive agents)

DIRECT approach Select appropriate initial antimicrobial therapy within 2 hours

Fig. 15.2  Diagnostic strategy for cancer patients with pulmonary infiltrates

FO-BAL ±other tests

Tests without FO-BAL

FO-BAL Make every effort to secure the procedure

If no diagnosis by day 3 and no clear improvement

:

If no diagnosis Consider lung biopsy

15  Minimally Invasive Diagnostic Strategy in Immunocompromised Patients with Pulmonary Infiltrates

Legionella pneumophila and Streptococcus pneu­ moniae and are being developed for other bacteria. It seems, however, that the incidence of these patho­gens may have been overestimated in haematological patients.

Legionella pneumophila Antibodies to Legionella pneumophila were first det­ ected using indirect immunofluorescence or microagglutination tests. Since then, numerous ELISAs based on different antigen-extraction methods have been developed. The reported sensitivities of these assays vary substantially, from 41% to 75% [47, 48]. Low titres of antibodies against Legionella spp. have been found in healthy volunteers, blood donors, outpatients, and hospitalised patients [49, 50]. These low titres seem to indicate previous exposure to Legionella spp. The urinary antigen test produced positive results 1–3 days after the clinical onset and remained positive for almost 1 year in a small proportion of patients [51, 52]. Importantly, the urinary antigen test showed greater than 99% specificity [53]. Sensitivity for L. pneumo­ phila infections ranged from 56% to 99% [54]. Low sensitivity of urinary antigen assays for serogroups other than L. pneumophila serogroup 1 has been reported, the range being 14–69% [55, 56]. In the future, an easy-to-perform PCR test with high sensitivity and greater than 99% specificity will probably become available on a wider scale [57].

Streptococcus pneumoniae The diagnosis of pneumococcal infection requires recovery of the microorganism from an uncontamina­

181

ted specimen (e.g., blood or pleural fluid). Blood culture results are positive in only about one-fourth of cases, and prior antibiotic therapy significantly reduces the proportion of positive blood culture results. Bacteraemia may be absent in 70–80% of cases of S.  pneumoniae pneumonia. Sputum cultures provide only a probable diagnosis, since S. pneumoniae carriage in the nasopharynx is common. PCR assays for S. pneumoniae have shown inadequate sensitivity when used on blood or urine and inadequate specificity for infection when used on respiratory samples. Several publications have described antigen detection assays. Good sensitivity and specificity have been reported with commercial kits for urinary C polysaccharide detection in adults. For example, the Binax NOW S. pneumoniae urinary antigen test was 82% sensitive and 97% specific when positive blood cultures were used as the reference standard. The test is simple to perform, detects the C polysaccharide cell wall antigen common to all S. pneumoniae strains, and provides results within 15 min. Urinary antigen was still detected in 83% of patients who were retested on treatment day 3 and persisted for at least 7 days in many patients [58]. Additional studies produced similar results (Table 15.5) [59–61]. A nested PCR assay targeting the pneumolysin gene was used to detect S. pneumoniae DNA in multiple sample types from 474 adults with community-acquired pneumonia and 183 control patients without pneumonia. The assay added little to information from existing diagnostic tests for S. pneumoniae and was unable to distinguish colonisation from infection when used on respiratory samples [59, 61]. Studies of S. pneumoniae antigen tests involving latex agglutination or counter-current imm­ unoelectrophoresis showed detection rates ranging from 0% to 88%, and specificity was often poorly defined.

Table 15.5  Binax NOW Streptococcus pneumoniae urinary antigen test: sensitivity and specificity Reference Type of infection Number of patients Sensitivity (%)

Specificity (%)

Smith, J Clin Microbiol 2003 [58]

Pneumococcal bacteremia

107

82

97

Murdoch, J Clin Microbiol 2001 [61]

Community-acquired pneumonia

420

80

100

Dominguez, Chest 2001 [60]

Bacteremic and nonbacteremic pneumonia

51

82

97

182

Mycoplasma pneumoniae The diagnosis of hard-to-culture pathogens such as Mycoplasma pneumoniae classically relies on testing paired sera to demonstrate a rise in the antibody titre. This method is of uncertain value in immunocompromised patients, most notably those with impaired cell-mediated immunity. Culturing is relatively insensitive and time-consuming, requiring up to 3 weeks for pathogen detection [62]. A number of PCR assays for M. pneumoniae have been evaluated in various respiratory specimens and patient populations, with promising results. PCR is more sensitive and considerably faster than culturing. In general, PCR results correlate well with serological results [63]. Both upper and lower respiratory tract samples are suitable for PCR testing. Upper respiratory tract samples (throat swabs and nasopharyngeal samples) may be the preferred sample types, as they are easy to obtain and ensure high sensitivity [59]. PCR on throat swabs may be the best existing diagnostic test for M. pneumoniae. However, standardised protocols will have to be developed before this test is recommended for widespread use [64].

Chlamydia pneumoniae Cell cultures for C. pneumoniae detection are technically demanding and time-consuming, and their yield is generally low. Therefore, the diagnosis of C. pneumoniae infection relies largely on serological testing, whose value in immunocompromised patients is uncertain. Furthermore, both acute- and convalescent-phase sera must be tested, which can only provide a retrospective diagnosis. These major limitations have prompted many studies of PCR for diagnosing C. pneumoniae infection. Unfortunately, the results have been conflicting. Overall, PCR was at least as sensitive as culturing, but its specificity was difficult to assess given the absence of an appropriate reference standard [59]. C. pneumo­ niae DNA can be detected in both upper and lower respiratory tract samples, but it is unclear which sampling site is better. Highly sensitive PCR techniques may increase the ability to detect C. pneu­ moniae carriage, the clinical relevance of which is unclear.

L. Camous et al.

15.4.1.2 Diagnosis of Viral Respiratory Infections Using Nasopharyngeal Aspirates In the past, viral cultures were the reference standard for the laboratory diagnosis of respiratory viral infections. However, 2–10 days were usually needed to obtain the results. To overcome this major limitation, faster diagnostic techniques, such as viral antigen detection, were introduced. These faster techniques are generally considered less sensitive and less specific than cell cultures. Moreover, viral antigen detection is not feasible for all respiratory viruses. PCR has proven extremely specific and sensitive for detecting respiratory viruses: it is now the reference standard for diagnosing respiratory viral infections and the only method available for detecting some viruses [39]. PCR was not only more sensitive than viral culture or antigen or antibody tests for detecting respiratory viruses in patients with haematological malignancies, but also decreased the time to diagnosis [65, 66]. Parainfluenza viruses 1–3, respiratory syncytial virus, rhinovirus, influenza viruses A and B, enteroviruses, and coronaviruses were reliably detected by PCR [67–69]. Nosethroat swabs yielded the same results with PCR as did BAL samples [39]. In a recent study of patients with haematological malignancies and respiratory viral infections, PCR on nasopharyngeal aspirates usually provided the diagnosis [70]. In the near future, widespread use of multiplex PCRs in patients with haematological malignancies will raise additional concerns about the relevance of virus retrieval from nasopharyngeal aspirates in patients with lung infiltrates [69]. Cytomegalovirus frequently causes severe disease after stem cell transplantation. The cytomegalovirus antigen assay is a rapid quantitative tool for monitoring cytomegalovirus infection. However, this method is tedious, as it requires counting the cells in the samples. In addition, the results may be influenced by factors such as storage and fixation methods. PCR assays have been used to diagnose cytomegalovirus infection. Real-time PCR provides a qualitative assessment of viral load. However, although the antigenaemia cutoff has been determined, the viral load cutoff is unknown [39, 71]. BMT recipients and patients with haematological malignancies who have severe impairments of cellmediated immunity are at risk for HSV pneumonia. Although HSV type 1 accounts for most cases, other

15  Minimally Invasive Diagnostic Strategy in Immunocompromised Patients with Pulmonary Infiltrates

herpes viruses such as cytomegalovirus, varicella zoster virus, Epstein-Barr virus, HHV-6, and HHV-8 are also common causes of pneumonia in this population. Advances in diagnostic techniques and the use of preventive or pre-emptive treatments have altered the epidemiology of some of the herpes virus infections. However, herpes viruses continue to cause significant morbidity and mortality in stem cell recipients [72]. A multiplex PCR assay designed to amplify herpes virus DNA in a diverse range of clinical specimens yielded higher detection rates for the viruses represented in the assay than did virus isolation and immunofluorescence-based antigen detection [73]. The turnaround time was far less than for the other techniques. Overall, the multiplex PCR detected substantially more herpes viruses, in some cases in specimens or at body sites where these viruses were found only rarely or never using conventional methods. Multiplex PCR has not yet been evaluated as a tool for diagnosing herpes virus pneumonia in patients with cancer. However, multiplex PCR may help to assess the pathogenic role for herpes viruses found in respiratory samples. An oligonucleotide microarray for herpes virus detection in clinical samples has been developed and needs to be evaluated in clinical practice.

15.4.1.3 Non-invasive Diagnostic Strategy for Diagnosing Pneumocystis Pneumonia (PCP) The standard method for diagnosing PCP pneumonia is microscopic identification of the organism using stains (methenamine silver, Giemsa, or toluidine blue O) or antibodies in BAL or induced sputum samples [74]. Several studies confirmed that PCR was more sensitive than microscopy for detecting P. jiroveci [75]. PCR is useful to rule out P. jiroveci infection in HIV-negative immunocompromised patients, who often have lower parasite counts than AIDS patients [43]. Nested PCR methods tend to have low specificity with high false-positive rates, whereas real-time PCR seems more specific [39, 76–78]. Samples similar to those used for microscopy can serve for PCR [75]. BAL specimens have the best yield; induced sputum samples, which are commonly used for HIVinfected patients, may be diagnostic but have not been evaluated in patients with other causes of immunodeficiency. [77]. Oral washes may be used as alternative

183

non-invasive samples, despite lower sensitivity of PCR compared to lower respiratory tract samples [42, 79]. In a recent study [80], 448 patients were screened for P. jiroveci pneumonia with PCR and GromoriGrocott staining. BAL was performed in 351 patients and induced sputum was diagnostic in 39 patients. PCR sensitivity was 87% and specificity was 92%, Negative predictive value on BAL samples was 98.7%. Given this excellent negative predictive value, we recommend PCR as the leading method for excluding PCP in cancer patients with pulmonary infiltrates. Negative PCR results on BAL fluid or induced sputum indicate that PCP treatment can be safely ­discontinued [81].

15.4.1.4 Diagnosis of Fungal Infection The diagnosis of invasive aspergillosis in haematological patients is often challenging. Until recently, only specimens from normally sterile sites were considered necessary for the definitive diagnosis of invasive fungal infections. Specimens from sites that may be colonised (e.g., sputum, BAL fluid, or sinus aspirate) were rarely diagnostic. BAL fluid cultures positive for Aspergillus spp. may indicate colonisation instead of invasive infection. Cultures may require days or weeks. The reference standard is histologically proven hyphal invasion in tissue specimens obtained by invasive procedures, but these may be deemed unsafe in patients with cytopenia [44, 82]. The first prospective, pathology-verified evaluation of a sandwich ELISA using a monoclonal antibody to galactomannan (GM) showed that serial monitoring was 92.6% sensitive and 95.4% specific [83]. The positive predictive value was 93%, and the negative predictive value was 95% [83]. In more than half the cases, antigenaemia was detected before invasive aspergillosis was suspected clinically [84, 85]. Based on this study and others, the European Organization for Research and Treatment of Cancer/ Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group convened a consensus panel to develop standard definitions for invasive fungal infections, introducing Aspergillus antigenaemia testing as an important diagnostic tool. The panel recommended that Aspergillus antigenaemia testing be used to support a probable diagnosis [44]. The value of this diagnostic strategy has been clinically validated [86, 87]

184

and shown to be clinically relevant. Moreover, the diagnostic yield of Aspergillus antigenaemia may be higher in neutropenic patients [88]. Finally, PCR has been used to detect Aspergillus spp., but false-positive results were noted, and no standardised commercial method is available [89–91].

15.4.1.5 Microbial DNA Identification by Blood PCR Numerous multivariate analyses have shown that inadequate antibiotic therapy in patients with severe sepsis is a strong and independent risk factor for death [92]. In clinical practice, diagnostic uncertainty regarding the causative microorganism leads to the use of broadspectrum combinations of antibiotics. The high selection pressure created by these combinations may lead to the emergence of multi-drug resistant bacteria. Moreover, in patients with haematological malignancies, who are often neutropenic, the diagnostic yield of blood samples is low (25% in one study [93] and probably even less in patients on concomitant antibiotic therapy), and more than half the clinically diagnosed infections are treated empirically. These data may reflect the presumed low bacterial/fungal load necessary for clinical infection. Therefore, rapid diagnostic tests are needed [94]. In recent years, several diagnostic tools based on culture-independent molecular biology-based techniques, such as real-time polymerase chain reaction, were developed [95]. However, their usefulness in clinical practice needs to be demonstrated. Numerous studies are ongoing. In severe sepsis [96], the match between PCR and blood culture results seems disappointing, with only 70% of positive PCRs in patients with positive blood cultures. However, positive PCR results showed statistically significant associations with higher organ dysfunction scores, as well as a trend toward an association with higher mortality. In immunocompromised patients, the results of preliminary studies of PCR seem more promising, although the true accuracy of these methods needs to be determined [97, 98]. PCR seems more sensitive than blood cultures, with a 100% match between positive blood cultures and positive PCR, as well as a high negative predictive value (98.6%) of negative PCR. However, these results require confirmation in larger studies, and their clinical usefulness needs to be tested in terms of antibiotic use and treatment reduction.

L. Camous et al.

15.4.1.6 Biomarkers ARF in cancer patients can be related to many conditions, including infections (opportunistic or bacterial) and non-infectious events (infiltration by malignant cells, drug-related pulmonary toxicity, or cardiogenic pulmonary oedema) [11]. Identification of the exact cause of ARF is associated with a marked improvement in survival. Rapid evaluation of the contribution of left ventricular failure to ARF enables prompt adequate treatment, obviating the need for invasive diagnostic procedures. Echocardiography is the reference standard for diagnosing left ventricular dysfunction but requires the availability of an experienced sonographer. B-type natriuretic peptide (BNP) is a predominantly ventricular cardiac hormone whose levels increase in the event of cardiac overdistension [99]. BNP measurement has been found highly sensitive and specific for the diagnosis of heart failure [100]. However, in the initial cohort, no cancer patients were included. The accuracy of BNP in cancer patients with ARF was evaluated in a recent study [101] of 100 patients. This study showed that BNP was useful only for ruling out a role for cardiac dysfunction in ARF, when NT-pro BNP was under 500 pg/mL (100% specificity and 100% negative predictive value). However, due to the direct cardiac toxicity of anti-cancer chemotherapy and high rate of renal failure among cancer patients, BNP elevation was not accurate for diagnosing cardiac dysfunction. The morbidity of anti-infectious treatment can be high. Systemic inflammatory response syndrome (SIRS) can be related to various causes (i.e., toxicity of chemotherapy), and a highly specific marker for sepsis would therefore be valuable. In non-neutropenic patients, procalcitonin (PCT), produced by the reticulo-endothelial cells, is a specific and sensitive marker for bacterial infections [102]. For example, PCT can differentiate between bacterial and viral meningitis. Data from neutropenic patients are scarce except in the paediatric population, where small studies [103, 104] suggested that PCT might be a good marker for bacterial sepsis with more than 95% negative predictive value and more than 85% sensitivity. In adults, no convincing data are available. Some studies in neutropenic patients [105] indicated that PCT was unhelpful (although we have personal data that seems somewhat more promising). Therefore, we cannot

15  Minimally Invasive Diagnostic Strategy in Immunocompromised Patients with Pulmonary Infiltrates

recommend PCT as a diagnostic tool in patients with haematological malignancies or other forms of cancer.

15.5 Conclusion and Avenues for Future Research The diagnostic and therapeutic impact of FO-BAL has been evaluated in several studies, and other diagnostic investigations have been evaluated individually. How­ ever, the routine use of all available investigations except FO-BAL has not been assessed, nor have the diagnostic strategy and outcomes been compared in cancer patients managed with versus without FO-BAL. The number of patients in whom non-invasive investigations obviates the need for FO-BAL may also deserve to be determined. In the future, the development of new tools will contribute to improve the diagnosis of bacterial pneumonia (16S RNA) and viral pneumonia (oligonucleotide microarray). These new tools can be expected to improve the diagnostic yield of BAL analysis, and nonbronchoscopic lavage may cause less respiratory deterioration than FO-BAL [106]. Markers for heart failure (brain natriuretic peptide) or bacterial infection (procalcitonin) need to be evaluated in cancer patients. We predict that advances in diagnostic tools will decrease the role for FO-BAL, just as in the past

Fever > 48h

CXR Normal HRCT

Normal Follow-up

Infiltrate Invasive procedure

Fig.  15.3  Recommendations from the Infectious Diseases Working Party of the German Society of Haematology and Oncology (Adapted from [45])

185

FO-BAL decreased the role for lung biopsy [107]. When the diagnosis remains uncertain despite extensive investigations including FO-BAL, the feasibility, safety, and diagnostic yield of lung biopsy should be evaluated, since identifying the cause of pul­ monary infiltrates is known to reduce mortality [11, 16].

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Pleural Effusions and Thoracentesis in Patients with Hematological Malignancies

16

Michael G. Alexandrakis, Paschalis Steiropoulos, and Demosthenes Bouros

Contents 16.1 Pleural Effusions in NHL....................................... 192 16.2 Pleural Effusions in Hodgkin’s Disease................ 194 16.3 Primary Effusion Lymphoma................................ 194 16.4 Castleman’s Disease................................................ 195 16.5 Pyothorax-Associated Lymphoma........................ 195 16.6 Multiple Myeloma................................................... 196 16.7 Pleural Effusions in Acute Leukemia................... 197 16.8 Pleural Effusions in Chronic Lymphocytic Leukemia................................................................. 197 16.9 Pleural Effusions in Chronic Myelogenous Leukemia (CML).................................................... 198 16.10 Pleural Effusions in Myelodysplastic Syndromes............................................................... 198 16.11 Pleural Effusions in Bone Marrow Transplantation....................................................... 199 16.12 Pleural Effusions Related to the Treatment of Hematological Malignancies........... 199 16.13 Thoracentesis.......................................................... 200 References............................................................................ 201

M.G. Alexandrakis Department of Haematology, Medical School, University of Crete, Heraklion, Greece e-mail: [email protected] P. Steiropoulos and D. Bouros (*) Department of Pneumonology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece e-mail: [email protected]; [email protected]

Pleural effusions are common in patients with malignancies. They can present as an isolated entity or be associated with parenchymal lung abnormalities. Patients with hematological malignancies (HM) can present with pleural effusion at diagnosis or may develop it during the course of their underlying disease [7, 21, 61, 68, 74]. Regarding etiology, various mechanisms can stimulate the accumulation of pleural fluid (Table 16.1) [74, 116]. The disease itself, drug-related pleural toxicity, radiotherapy, infections, secondary malignancies, autoimmunity, extramedullary hematopoiesis and other complications may contribute to the development of pleural effusions in patients with HM [72, 156, 188, 242]. Pleural effusions have been reported in up to 20% of patients with non-Hodgkin’s lymphomas (NHL), although effusions are uncommon in the peritoneal and pericardial cavities (Table 16.2) [15, 45, 56, 74, 160, 203]. The second most common condition is bone marrow transplantation (BMT), while acute and chronic leukemias, myelodysplastic syndromes (MDS), multiple myeloma (MM) and other hematological disorders are rarely accompanied by pleural effusions [4, 7, 52, 61, 79, 84, 100, 107, 189, 200, 220, 234]. Routine analysis of the pleural fluid for pH, LDH, protein and cholesterol should be performed, since application of the Light’s criteria is useful in distinguishing transudative from exudative pleural effusions (Table 16.3) [140]. Morphological examinations by light microscopy, flow cytometry and in selected cases gene rearrangement studies are useful to document the malignant nature of a pleural effusion [80, 116, 159, 242]. Examination of cytocentrifuged specimens in the hematology laboratory is superior to cytopathological examination for HM [13, 15, 126]. In selected cases of undiagnosed patients, pleural biopsies by needle or thoracoscopy are occasionally indicated [17, 134, 171, 218, 237].

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_16, © Springer-Verlag Berlin Heidelberg 2011

191

192 Table  16.1  Mechanisms of pleural effusions in patients with hematological malignancies   1. Infiltration by the malignancy (direct invasion with shedding of malignant cells into the pleural space)   2. Compression by the malignancy (impairment of fluid efflux from the pleural space by lymphatic obstruction)

M.G. Alexandrakis et al. Table 16.3    Pleural fluid tests that are useful for the etiological diagnosis of pleural effusion Always useful (routine tests) Pleural pH Pleural LDH and protein rates (Light’s criteria)

  3. Obstruction of the pulmonary and mediastinal lymph nodes and/or thoracic duct obstruction resulting in chylothorax

Morphological examinations by light microscopy in hematological laboratory (with immunophenotyping)

  4. Drug-related pleural toxicity and radiation therapy

Pleural cholesterol

  5. Infections

Flow cytometry when cytologic diagnostic is positive (may disclose clonal lymphocytes in the pleural fluid with identical phenotype in case of direct invasion for a lymphoma)

  6. Pulmonary embolism   7. Bleeding   8. Cardiac insufficiency, hypoalbuminemia from liver or renal insufficencies   9. Capillary-leak syndrome with cytokine production 10. Other complications (secondary malignancies, autoimmunity, extramedullary hematopoiesis in CML, amyloidosis, plasmacytoma, granulocytic sarcoma, veno-occlusive disease and urinothorax, etc.)

Sometimes useful

May be useful in selected cases PCRs to viruses that promote oncogenesis (HHV8, EBC, CMV, etc.) Gene rearrangement studies Immunoglobulin and TCR rearrangements Cytogenetics and molecular studies Studies of oncogenes expression

Table 16.2  Malignancies associated with pleural effusion Situations in which pleural effusions are common

Needle pleural biopsies Pleural biopsy by pleuroscopy or thoracoscopy

•  Non-Hodgkin’s lymphoma (up to 48% of the patients) • Hodgkin’s disease (about 30% of the cases, most frequently associated with pulmonary involvement) •  Allogeneic and autologous BMT Situations in which pleural effusions are uncommon •  Acute and chronic leukemias •  Myelodysplastic syndromes

to chemical pleurodesis include response to therapeutic thoracentesis, the patient’s general health, i.e., performance status, pleural space elastance, underlying malignancy and pH of the pleural fluid [100, 200]. When the pleural effusion is due to lung infections, cardiac failure, etc., treatment of the underlying condition usually leads to resolution of the effusion.

•  Multiple myeloma (mostly in IgA myeloma)

Careful evaluation of the pleural effusion to establish its etiology is required to direct therapy [79]. Effusions may result from direct pleural invasion or indirect effects (paraneoplastic effusions), such as impairment of fluid efflux from the pleural space by lymphatic obstruction or pleural effects of cancer radiation or drug therapy. Disease improvement is accompanied by resolution of the effusion [7, 100]. Recurrent resistant effusions may need pleurodesis (e.g., talk, tetracyclines, bleomycin) or local treatment with biological agents (bortezomib or rituximab) [8, 22, 100, 134, 142, 150, 221]. Factors that should be considered prior

16.1 Pleural Effusions in NHL Pleural effusions are a common complication of NHL, occurring in up to 48% of the patients [7, 21, 61, 74, 75]. Pericardial and peritoneal effusions are much less common complications of malignant lymphomas. In one study, pleural effusions were present in 8.6% of NHL patients, whereas pericardial effusions and ascites occurred in only 0.8% each [62, 233]. The frequency of development of pleural effusions differs among the various sub-types of NHL [45, 62, 97, 110, 152, 180, 239]. Thus, T-cell lymphomas are associated with effusions

16  Pleural Effusions and Thoracentesis in Patients with Hematological Malignancies

much more frequently than B-cell lymphomas [35, 63, 88, 115, 230]. Moreover, lymphomatous ­effusions show substantial age and sex variation [116]. Among malignant pleural effusions, lymphoma/leukemia appears to be more frequent in males (21.1% versus 8% in females) [116]. In a study of malignant pleural effusions in children and young adults, there was a predominance of lymphoma/leukemia cases [98]. In another study, malignant pleural effusions were seen with higher frequency (64.5%) in patients >40 years of age, although lymphoma was the underlying hematological malignancy in only 4.1% of them [194]. Most patients with primary mediastinal B-cell lymphomas have stage I-II disease, yet bulky disease with associated pleural or pericardial effusions occurs in approximately a third of the patients [147]. Diffuse large B-cell lymphoma is the most frequent NHL subtype associated with lymphomatous pleural effusions [86]. Advanced stage III and IV small lymphocytic lymphomas are also associated with pleural effusions due to pleural infiltration [47, 61, 126, 220]. Rarely, pleural effusions have been reported to accompany monocytoid B-cell lymphoma, a low-grade B-cell malignancy that often involves regional lymph nodes and the salivary glands, and rarely the spleen and/or the bone marrow [188, 211]. Pleural effusions can be unilateral or bilateral, while the origin of the monocytoid B-cell lymphocytes obtained by thoracentesis can be confirmed by appropriate immunophenotyping [188]. Although the lung is frequently involved in disseminated lymphomas, isolated primary pulmonary lymphomas occur, but are rare. The most common histological subtype is a pleural low-grade extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL/MALT type) [53]. An entire chapter of this book from Wilsez and colleagues is dedicated to this entity. Common presenting features include cough, dyspnea, chest pain, fever and hemoptysis, or it can be an incidental finding on a chest radiograph obtained for other reasons. A safe distinction between EMZL/MALT and lymphoplasmacytic lymphoma (LPL) of the pleura with associated pleural effusion cannot be made based on morphological and immunohistochemicalal characteristics alone, since both are small B-cell proliferations with similar immunohistochemical profiles [153]. At the time of diagnosis, LPL is frequently characterized by infiltration of the bone marrow, lymph nodes and spleen. In contrast, EMZLs usually involve extranodal tissues first [5, 133, 153]. In difficult cases, cell chromosomal

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analysis and detection of t(14:18) (q32;q21) that involve IGH and MALT 1 are useful in differentiating LPL from MALT [94, 153]. Other types of primary pleural NHL are rare, and available clinical information is based on small observational studies and case reports [126, 220]. In most cases, pleural effusions result from lymphomatous pleural infiltration, while the fluid is typically serous or serosanguinous and located on one or both pleural cavities. Symptoms include dyspnea, cough and chest pain [45, 74, 160]. Rarely, NHL patients with large pleural effusions present with shortness of breath requiring immediate thoracentesis for removal of an adequate amount of fluid prior to initiation of appropriate therapy. In NHL patients with pleural effusion, fluid accumulation can be unilateral or bilateral. T-cell neoplasms, especially lymphoblastic lymphomas, are frequently associated with mediastinal masses and pleural effusions [61]. In rare cases, fluid may be chylous [21, 74]. In rare cases of advanced low-grade lymphomas, pleural effusion can be a transudate due to venous compression, cardiac or renal failure or associated hypoalbuminemia [202]. Recently, a rare case of urinothorax due to ureter obstruction was reported in a patient with NHL [123]. Transudative or exudative reactive pleural effusions have also been observed to accompany lung involvement in lymphomas [12, 184]. Pleural effusions in patients with lymphomas can develop by one or more mechanisms including pleural infiltration with shedding of malignant cells into the pleural space, lymphatic obstruction of the pulmonary and mediastinal lymph nodes, and/or thoracic duct obstruction resulting in chylothorax [21]. Lymphomatous involvement of the pleura is characterized by presence of clonal lymphocytes in the pleural fluid with an identical phenotype to that seen in lymphocytes obtained from affected lymph nodes [15, 45, 96]. On the other hand, in cases of reactive pleural effusions, lymphocytes are polyclonal, small, mature and predominantly of T-cell origin [12, 15, 137]. Difficulties exist in distinguishing neoplastic from reactive lymphocytes in cytopathological specimens, especially in cases of small lymphocytic/ lymphoblastic lymphomas [15]. Flow cytometry, immunohistochemistry, immunoglobulin and TCR rearrangements, cytogenetics and studies of oncogenes expression are useful for diagnostic purposes [15, 148, 151, 160].

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Cytological evaluation with immunophenotyping of the pleural fluid cells is usually diagnostic of the specific NHL subtype [15]. Various lymphoma subtypes with characteristic cytomorphology have been reported with serous effusions and include Burkitt lymphoma [97], marginal zone lymphoma [58], multilobated type NHL [152], peripheral T-cell NHL [110] including Sézary syndrome [238] and anaplastic large cell lymphoma [115]. Immunological studies define the B- or T-cell origin and degree of maturation. The majority of adults with NHL and pleural effusions have disease of an intermediate grade, a small proportion have low-grade NHL, and an even smaller proportion suffer from high-grade lymphomas [133, 188]. Regarding prognosis, the presence of pleural effusion can influence overall survival depending on the time of diagnosis [74]. In patients with intermediategrade NHL, the presence of a pleural effusion at the time of presentation does not seem to affect overall survival [74]. On the other hand, the presence of pleural effusion at the time of presentation was associated with extremely poor outcome in a study of 57 patients with primary mediastinal large-cell and immunoblastic lymphomas [130]. In another study of 91 patients with low-grade follicular lymphoma, the presence of pleural effusion was a factor adversely influencing overall survival along with age >70 years, presence of B symptoms, histological subtype of follicular mixedcell NHL, tumor size >10 cm, >2 extranodal sites of disease, and stage III and IV disease according to the Ann Arbor lymphoma staging system [158]. In a retrospective study, the effects of the biochemical and cytological properties of the pleural fluid on the survival of 284 patients with malignant pleural effusions were determined. Tumor type, as well as some laboratory features of the pleural fluid, such as pH, LDH and protein concentration, influenced survival [22]. Lastly, a retrospective multicenter study analyzed the clinical features and treatment outcomes of B-lymphoblastic lymphoma (B-LBL) and T-lympho­ blastic lymphoma (T-LBL) in 55 newly diagnosed patients (45 T-LBL and 10 B-LBL). With the exception of the more frequent involvement in T-LBL, there were no differences in the clinical features between the two subtypes. Clinical outcome of T-LBL versus B-LBL in terms of response and survival was not significantly different, although the presence of pleural effusion was prognostic for overall and progressionfree survival [49].

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16.2 Pleural Effusions in Hodgkin’s Disease Pleural effusions are common in patients with Hodgkin’s disease (HD), whereas pleural effusions occurred in approximately 30% of thoracic HD cases [7]. Although thoracic duct obstruction and impaired lymphatic drainage due to enlarged hilar or mediastinal lymph nodes appear to be the primary mechanism of pleural effusion in HD [61], in some cases fluid accumulation may be due to direct pleural involvement by the tumor [23, 61]. Pulmonary parenchymal disease occurs in 38% of patients with HD and is invariably associated with mediastinal lymphadenopathy and widespread disease [7]. HD rarely affects the pleura alone, and when this happens it is the result of advanced local disease, as demonstrated by thoracic CT scans [23, 183]. Few studies exist regarding immunohistochemistry in the diagnosis of HD associated with serous effusions. Look-a-like of Reed–Stenberg cells (R-S) in pleural effusion cytology can lead to incorrect diagnosis [61, 183]. Hence, in order to avoid these pitfalls, a combination of immunocytochemistry, flow cytometry, cytogenetics and molecular studies should be applied [61, 124, 183].

16.3 Primary Effusion Lymphoma Primary effusion lymphoma (PEL) is a rare subtype of B-cell lymphomas that presents as pleural, peritoneal and pericardial neoplastic effusions in the absence of a distinct tumor mass or recognizable nodal involvement [32, 39, 42]. This body cavity-based lymphoma is associated with herpesvirus-8 (HHV8) infection, also termed Kaposi sarcoma herpesvirus (KSHV) [31, 39, 40, 44, 167]. HHV8 was initially identified in tissue biopsies of patients with AIDS-related NHL as pleural, peritoneal and pericardial lymphomatous effusions [4, 167, 229, 244]. Nowadays, PEL is considered to be an HHV8driven malignancy [32, 39, 42]. Viral presence in the neoplastic cells can be demonstrated by immunohistochemical methods using the HHV8 LNA-1 latent protein antibody or other molecular methods [32, 167]. The majority of PEL cases affect HIV-positive patients,

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although several cases have been described in patients with cancer, cirrhosis or underlying immunosuppression because of solid organ transplantation [40]. In the general population, PEL develops in older individuals living in areas with a high prevalence of HHV8 infection [39, 208]. Few cases of PEL in HIV-negative patients have been reported, and some of them were not associated with HHV8 [40, 90, 108, 212, 229, 244]. The etiological agent(s) responsible for these HHV8-negative cases remain(s) unclear [39]. Most (>90%) HIV-positive cases of PEL also show evidence of EBV infection, suggesting that EBV plays a supportive role in malignant cell transformation [105, 229]. Interestingly, HHV8, like EBV, belongs to the gamma herpesvirus family. HHV8 has also been identified in patients with multicentric Castleman’s disease (MCD), as will be discussed next [51, 217]. The mechanism by which HHV8 promotes oncogenesis in PEL is unclear [118]. Nowadays, it is accepted that PEL is a large-cell lymphoma derived from post-germinal center B-cells with an intermediate immunophenotype between immunoblasts and plasma cells [41]. Hence, PEL cells express activation and plasma cell markers such as CD30, CD38 and CD138 [38, 41, 131], whereas routine B-cell (CD19, CD20, CD79a) and T-cell (CD3, CD4, CD8) markers are typically absent [31, 32]. Rarely, PEL cells aberrantly express T-cell markers and rearrangements of the T-cell receptor gene [31, 179, 201]. Regarding PEL prognosis, it is extremely poor, with a median survival of <6  months [215]. Modern antiretroviral treatment appears to improve prognosis [27, 102].

16.4 Castleman’s Disease Castleman’s disease (CD) is a rare lymphoid disorder of unknown etiology that is characterized by massive lymphadenopathy, anemia and hypergammaglobulinemia. It is also known as angiofollicular lymphoid hyperplasia, giant lymph node hyperplasia and Castleman’s lymphoma. Three distinct histological variants exist: plasmacytic, hyaline vascular and intermediate [14]. Although CD is most frequently found in the mediastinum, it has also been identified in other anatomical sites such as the neck, pelvis and axilla [191]. Localized CD (or type 2) is usually of the hyaline-vascular type, is

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located in the mediastinum (79% of cases) and can be cured by surgical excision alone. Pleural effusions in this subtype are due to local compression [14]. Contrary to the benign clinical course of most cases of hyalinevascular CD, the plasmacytic (type 1) MCD is typically much more aggressive. It usually presents with fever, rash, cytopenias, hypergammaglobulinemia and extensive lymphadenopathy. This form is common in patients with AIDS. HHV8 is causally associated with MCD, since it is present in 95% of HIV-positive patients [91, 191]. Pulmonary symptoms and infiltrates are common, especially in HIV-associated multicentric CD [1, 95, 181]. The most frequent pulmonary manifestation is an acute febrile interstitial pneumonitis typically associated with high fever, weight loss and malaise [95]. The role of various pro-inflammatory cytokines, such as IL-6 and IL-10, has been studied and appears crucial during disease exacerbations [173, 182]. Overproduction of such cytokines is responsible for a nonspecific capillary-leak syndrome, as has been studied in critically ill patients [43, 82]. The extensive angiogenesis seen in CD supports the hypothesis that VEGF participates in the pathophysiology of the disease [43]. Pleural effusions have been described in MCD and are sometimes chylous [26, 228].

16.5 Pyothorax-Associated Lymphoma Pyothorax-associated lymphoma (PAL) is a distinct type of B-cell NHL that develops in the pleural cavity of patients with chronic pyothorax [87]. It is strongly associated with EBV infection based on the elevated values of serum anti-EBV antibodies, the presence of EBV genomes in the nuclei of tumor cells and the expression of latent infection genes, such as EBNA2, in most patients [122, 170, 178]. HHV8 is not detected in all cases of PAL [176]. Artificial pneumothorax has been found to be a significant risk factor for the development of PAL among chronic pyothorax patients [11]. It is of interest that there are no reports of pleural neoplasia in chronic pyothorax patients after surgical resection of the pyogenic pleural membrane [11, 170]. Repetitive chest radiographs for the artificial pneumothorax may be linked with PAL development due to excessive radiation exposure [104]. Overall prognosis in patients with

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PAL is poor. Several factors, such as poor performance status, high levels of ALT and blood urea nitrogen, are associated with worse survival among PAL patients [11, 104]. Recently, a case of PAL of T-cell origin was reported. Tumor was arising from the chest wall, and development followed the therapeutic pneumothorax for pleural tuberculosis [204].

16.6 Multiple Myeloma MM is a malignant neoplasm of plasma cells that usually invades the bone marrow, but may involve other body sites. Pleural effusions occur in approximately 6% of patients with MM during the course of the disease [187, 199]. The etiology of pleural effusions is multifactorial, and effusions due to pleural myelomatous involvement are rare, occurring in <1% of the cases [7, 199]. The following mechanisms have been implicated in the production of pleural fluid: infiltration of the pleura by malignant plasma cells (i.e., myelomatous pleural effusion), infiltration of the pleural fluid from adjacent affected tissues, renal dysfunction due to infiltration with paraprotein of the renal tubular system with development of glomerular damage, pulmonary embolism, congestive heart failure secondary to amyloidosis, secondary neoplasms and mediastinal lymph node infiltration with accompanying lymphatic obstruction [7, 144, 172, 187]. Among myelomatous pleural effusions, 80% occur in IgA MM, possibly as a result of this type’s major tendency to invade extraosseus structures [120, 199, 205]. The remaining cases are IgG MM [199, 205]. Rare cases of IgD MM with associated pleural effusion have also been described [243]. Bence Jones protein type and IgE MM are rarely associated with pleural effusions [243], whereas IgM-type MM is associated with pleural effusions in 5–13% of the cases [9, 112]. Pleural effusion due to MM invasion is rare. When myelomatous effusion is present, outcome is poor with median survival of <4 months. Plasmablastic myeloma is a subtype of MM that is characterized by distinctive morphological features. This subtype is usually associated with renal insufficiency and survival of <6 months [48]. Pleural effusions due to infiltration by malignant plasma cells can occur at any time during the clinical course of the disease, i.e., they can precede clinical diagnosis or develop after treatment’s initiation [92, 109].

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Although various tests in addition to morphological evaluation have been used in the diagnosis of myelomatous effusions, immunophenotypic analysis of the infiltrating plasma cells is most important for diagnostic purposes [25, 240]. Extramedullary plasmacytoma comprises approximately 4–6% of plasma cell malignancies [169, 186]. Few cases of extramedullary plasmacytoma arising in the mediastinum have been described [186]. Direct extension of the plasmocytoma into the pleural space may result in development of pleural effusion [169]. Amyloidosis, a well-described complication of MM, can in rare cases involve the pleura with resultant transudative or exudative effusions. Diagnosis of pleural amyloidosis by biopsy is important because the disease is usually refractory to conventional treatment and may necessitate pleurodesis [143]. In a retrospective study of 35 patients with biopsy-proven pulmonary amyloidosis, 5 (14%) were found to have associated MM [232]. Waldenstrom’s macroglobulinemia (WM) is a relatively rare disorder characterized by lymphoplasmacytic monoclonal proliferation and a high amount of monoclonal serum IgM. In rare cases pleural involvement can occur, and is characterized by identification of lymphoid and plasmacytoid cells in the effusion along with the presence of monoclonal IgM in cellfree suspensions [76]. Pulmonary involvement in WM is relatively rare, occurring in 3–5% of the cases. It usually presents with pulmonary nodules, masses, diffuse infiltrates or pleural effusions [125]. Morphological examination of disease-related small lymphocytes in the pleural effusion is nondiagnostic, rendering flow cytometry and gene rearrangement studies invaluable for accurate diagnosis [125, 146]. In a study of 44 patients with WM with associated pulmonary disease, the authors found that although 15% of the patients had no pulmonary symptoms at diagnosis, two thirds of those with lung disease presented with abnormal findings on chest radiograph. The radiographic findings were initially described as reticulonodular infiltrates, confluent masses or pleural effusions. In 39 patients there was pathologically confirmed lung involvement with WM, a much higher incidence than the 0–5% reported by other groups [196]. In another autopsy study, pathological lung involvement was detected in 16 of 32 patients with WM, despite the absence of respiratory symptoms p­ remortem [241].

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Although open lung biopsy can confirm lung and pleural involvement in patients with WM, most cases are diagnosed by transbronchial or pleural biopsy or by thoracentesis [76, 81].

16.7 Pleural Effusions in Acute Leukemia Pleural effusions in acute myeloid or lymphoblastic leukemia are relatively rare [7], despite the fact that microscopic infiltration of the pleura is a common finding at autopsies of patients with leukemia [71]. Leukemic infiltrates in other tissues were found at autopsy in 10 of 15 patients with acute leukemia who died of an unrelated cause during complete bone marrow remission [207]. Moreover, pleural involvement can accompany bone marrow involvement [71, 197]. In these cases, pleural effusion is typically hemorrhagic or has features of empyema reflecting underlying infections [55, 60, 155, 224]. In other cases, hypoalbuminaemia, cardiac or liver failure contributes to the development of pleural effusion [60]. Cases with pleural involvement at presentation are rare, and the same is true for pleural involvement as the only site of extramedullary relapse [70, 77, 78, 219]. As long-term survival in patients with acute leukemia is increasing, unusual sites of relapse are now more frequently recognized [34, 197]. CNS and testes have long been recognized as the most common sites of extra-medullary relapses in acute leukemia [71, 207]. Granulocytic sarcoma is a solid tumor composed of malignant myeloid cells. It constitutes the solid variant of acute myelogenous leukemia (AML). Primary granulocytic sarcoma of the pleura has been described [71, 77, 207]. Recently, a case of cardiac myeloid sarcoma with associated pericardial and bilateral pleural effusions was described [198]. Most cases reported in the literature concern acute lymphoblastic leukemia (ALL). Typing and differentiation of the cells of the pleural effusion can be difficult. Combined cytomorphology and immunophenotyping lead to correct diagnosis. Rarely, invasive procedures (pleural biopsies) are required for diagnosis [77, 78, 106]. T-LBL is a rare malignancy that accounts for 2–4% of adult NHL [111]. It is much more common in teenage adolescents. At presentation, there is bulky mediastinal involvement frequently associated with pericardial or pleural effusion. In one study, bulky mediastinal

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involvement with associated pleural effusion was found in about half the patients [138]. In another study, 95% of the 45 patients showed a mediastinal mass at diagnosis, and 40% had concurrent pleural effusion [103]. Unusual cases of pleural effusions with a lymphomatous mediastinal mass of pre-B cell origin and a normal hemogram have been described [189]. According to recent studies, the balance of matrix metalloproteinases plays an important role in the mechanism of leukemic infiltration into extramedullary organs [223]. Other investigators have suggested that the chemokine receptor CXCR4 and its ligand are involved in extramedullary invasion and that VEGFR1 controls the onset of extramedullary disease in ALL [59, 83]. The prognostic significance of pleural effusion at diagnosis in patients with acute leukemia is not well defined. Some investigators claim that it does not affect the rate of hematological remission and survival, while others report a worse prognosis, especially in plasmacytic and hairy cell leukemias [30, 149]. These latter two forms of leukemia can present with pleural effusions that contain typical leukemic cells. In these cases, aggressive treatment is indicated [30, 149]. Pleural effusions in patients with acute leukemia usually disappear quickly after induction chemotherapy. On the other hand, recurrence of pleural exudates is inevitable in those who do not achieve remission. In such cases, respiratory failure due to rapid fluid accumulation can develop, necessitating local treatment with intrapleural chemotherapy, pleurodesis or repeated drainage [2, 33].

16.8 Pleural Effusions in Chronic Lymphocytic Leukemia Effusions in chronic leukemias, although rare, are more common than in acute leukemias [10, 28, 157, 216]. In chronic lymphocytic leukemia (CLL) the most common cause of pleural effusion is pleural infiltration, a condition that predisposes to transformation to more aggressive lymphoid neoplasms, such as Richter’s syndrome or to prolymphocytic transformation [213]. An entire chapter on pulmonary involvement in CLL has been provided by Dr. Wadwha and colleagues in this book. In a large retrospective study of patients with CLL, diverse pulmonary complications were reported in 223/1,000 admissions [6]. Infections were the most frequent complications with the lung as the

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major site [20, 161, 162]. Pleural involvement by leukemic cells was the second most common complication in 9% of the patients. Studies of patients with CLL show lung involvement in up to 40% of the patients [16, 20]. When the effusion is the result of leukemic pleural infiltration, the fluid is likely to be hemorrhagic and contains malignant lymphocytes that are identical to those found in blood and bone marrow [235]. The differential diagnosis of pleural effusions in patients with CLL includes primary pleural involvement, central lymphatic obstruction, infections, and changes induced by previous radiation or chemotherapy [235]. Immunohistological methods can be used to determine the nature of the pleural effusion [154]. Pleural involvement in B-CLL leads to accumulation of fluid rich in monoclonal B cells, whereas in most reactive pleural effusions, T cells and a small proportion of polyclonal B cells are found. Although the clonality and immunohistochemistry of the lymphocytes that are isolated in the pleural fluid can provide a definitive diagnosis, there are reports showing that lymphocytic infiltration by B-CLL leads to reactive pleural effusions with predominant polyclonal T cells [18, 154]. A high proportion of T cells with monoclonal T-cell receptor rearrangements is characteristic of T-cell neoplasms [154]. Patients with CLL and pleural involvement usually have long-standing disease prior to development of pleural effusion [235]. If tuberculosis is suspected in a patient with known CLL and concurrent pleural effusion, pleural biopsy or thoracoscopy is indicated in order to differentiate tuberculosis from lymphocytic pleural infiltration [225, 235].

16.9 Pleural Effusion in Chronic Myelogenous Leukemia (CML) The most common cause of pleural effusion in chronic myelogenous leukemia (CML) is extramedullary hematopoiesis, although the pleura are an uncommon site [29, 67]. Frequently, all granulocytic precursors and a few blasts are found in the pleural fluid of patients with CML [157]. Regarding the formation of exudative pleural effusions, there are several possible mechanisms. The first is leukemic infiltration. The fluid is usually hemorrhagic, while pleural infiltration frequently appears shortly before transformation into

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acute leukemia. In these cases, the pleural fluid contains a greater proportion of blasts [54, 117, 129]. Isolated pleural blast crisis in the absence of medullary transformation is extremely rare [117]. Pleural reaction secondary to intrapleural bleeding is another possible mechanism [113]. Various factors may have a role in hemorrhagic effusions, such as leukostasis and platelet dysfunction. Obstruction of pleural capillaries or infiltration of interstitial lung tissue by leukemic cells during unrestrained leukocytosis along with increased capillary permeability because of cytokine production can also mediate the development of pleural effusion [101, 222]. Infections may play an additional role. Other chronic myeloproliferative diseases may be associated with pleural effusions, such as systemic mastocytosis, chronic eosinophilic leukemia, myelofibrosis and polycythemia vera. The most common cause of pleuritis in these patients, other than lung infections, is extramedullary hematopoiesis and leukemic transformation with associated infiltration [54]. Pleural effusions can also be reactive. In these cases, they contain a mixture of macrophages, mesothelial cells and T-lymphocytes [168, 192].

16.10 Pleural Effusions in Myelodysplastic Syndromes Pleural effusions in MDS are rare and usually associated with underlying lung infections. Pleural effusions secondary to leukemic infiltration are a rare initial manifestation of MDS patients [145, 166]. In patients with chronic myelomonocytic leukemia (CMML), pleural effusions are rare and usually respond to appropriate antileukemic therapy [29]. The prognostic significance of extramedullary involvement in patients with CMML has not been well determined. However, most consider it as a sign of advanced disease and recommend aggressive therapy [29, 145] The presence of extramedullary disease in MDS has been well documented in CMML with disease progression [145]. Immunological disorders (defective B-, T- and natural killer-cell function) are frequent in patients with MDS. Increased or decreased levels of immunoglobulins and monoclonal gammopathy may also be found in patients with MDS [121]. Pulmonary vasculitis or eosinophilic infiltrations of the lungs complicated by

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pleural effusion are additional causes of morbidity and mortality in these patients [24, 165]. MDS patients are also susceptible to pulmonary and disseminated fungal infections because of defective cell-mediated immunity, as shown by a low blood CD4 lymphocyte count [50, 121, 226].

16.11 Pleural Effusions in Bone Marrow Transplantation Infectious and noninfectious complications occur in 40–60% of all BMT recipients with considerable associated morbidity and mortality [46]. Various factors are thought to play an important role in the manifestation of pulmonary complications including immunological defects secondary to the underlying disease and its treatment, the conditioning regimen and development of graft-versus host disease (GVHD) [119]. Information concerning pleural involvement after BMT is limited. In one study 16% of patients developed pleural effusions within the first 100  days after BMT [175]. Pleural effusions may accompany various potentially life-threatening complications that are associated with BMT, such as infections [175], venoocclusive disease (VOD) [185], G-CSF toxicity [73], acute and/or chronic GVHD [209], and recurrence of the underlying hematological disease [139]. Multiple effusions appear to be part of the presentation of severe acute or chronic GVHD, often in association with CMV disease in patients who receive allogeneic donor marrow [209, 231]. In these latter cases, CD8+/HLA-DR + lymphocytes expressing CD57 predominate in the pleural fluid [139]. The most common noninfections causes of pleural effusion in BMT recipients are aggressive fluid resuscitation, including use of blood products. Effusions are usually right-sided or bilateral [128]. Other noninfections causes of pleural effusions in BMT recipients include effusions after conditioning with cyclophosphamide and total-body irradiation [164, 175, 190, 206]. In patients with extensive chronic GVHD, isolated effusions have been reported [214]. In these cases, the term serositis has been used to describe the sterile nature of these effusions [139, 206, 214]. Hepatic VOD is a complication of patients treated with chemotherapy and radiation therapy, and pleural effusions have

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been reported in up to 50% of BMT recipients who develop VOD compared to 3% of BMT recipients without VOD [185]. It is of interest that the affected patients have minimal or no respiratory symptoms. Post-transplantation lymphoproliferative disorder (PTLD) due to reactivation of EBV has also been occasionally associated with pleural effusions and CD4+ lymphocyte expansion. These patients are frequently resistant to immunosuppressive therapy [139]. PTLD includes a spectrum of lymphoid proliferations ranging from benign reactive lymphoid hyperplasia to high-grade NHL, usually of B-cell immunophenotype, although cases with T or null immunophenotype have also been reported [99, 115, 132]. The pathophysiological mechanism is poorly understood, and the clinical manifestations include in addition to pleural effusions, excessive weight gain, ascites, fever, rash, hypotension and edema associated with kidney and liver abnormalities indicative of a common injury to multiple organs [36, 177]. About 50% of allogeneic or autologous BMT recipients develop noncardiogenic pulmonary edema with or without pleural effusions and half of them have associated hepatic, renal or CNS abnormalities. These observations suggest that circulating leukocytes play an important role in the development of the syndrome [36].

16.12 Pleural Effusions Related to the Treatment of Hematological Malignancies All-tran-retinoic acid (ATRA) is a potent differentiation agent that is an effective therapy in patients with acute promyelocytic leukemia (APL). Up to 50% of APL patients treated with ATRA may develop a lifethreatening complication of uncertain pathogenesis that is characterized by fever, respiratory distress, pulmonary infiltrates, weight gain, pleural and pericardial effusions, renal and cardiac failure, edema and thromboembolic events. Some patients require mechanical ventilation and/or dialysis [136]. Infiltration of the lung parenchyma as well as pleural infiltration by maturing malignant promyelocytes has been implicated in the development of pulmonary capillaritis and pleuritis [37, 64, 65, 174, 227]. Other chemotherapeutic agents, such as high-dose cytarabine, have also been associated with the development of pleural

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effusions. Pathogenesis remains unclear, but is likely due to direct toxic and immunological mechanisms. Tyrosine kinase inhibitors (TKIs) (imatinib, nilotinib and dasatinib) have revolutionized the treatment of CML and are increasingly used in other malignancies [89]. Despite the apparent selectivity of these agents, side effects can occur because of off-target kinase ­inhibition [93, 127]. Clinical consequences are edema, pleural and pericardial effusions. These effusions are mainly associated with dasatinib, occurring much less frequently with imatinib or nilotinib therapy [193]. Regarding dasatinib, the cumulative incidence of pleural effusion at 1  year was 29.5% (95% CI 18.6– 43.3%), and pleural effusions occur in 14–35% of CML patients who receive it [66]. Several risk factors have been proposed, but the etiology of the effusions remains unclear. Risk factors are blastic-phase CML, advanced age, previous history of cardiac disease, hypertension, hypercholesterolemia, underlying lung disease, fluid retention, and history of autoimmune diseases and of skin rashes [66, 141]. Pleural effusion was less frequent with once daily dosing than with twice daily dosing (all grades, 18% versus 32%). Dasatinib-induced pleuritis may be related to inhibition of PDGFR-B, which is expressed in pericytes and involved in angiogenesis [114]. Others suggest an immune-mediated mechanism based on the high lymphocyte content of the pleural fluid in these patients, the presence of autoantibodies and the response to corticosteroids [19, 195]. Radiation therapy to the thorax is frequently administered in patients with lymphomas and can be complicated by development of pneumonitis, pleuritis or pericarditis. Pleural effusions as complications of radiation therapy are the result of radiation pleuritis or of lymphatic obstruction from mediastinal fibrosis [135, 163]. Pleural effusions secondary to radiation are usually observed within 6 months following radiotherapy, although some cases occur several years later [163]. Another complication of mediastinal radiation is the development of chylothorax many years after radiotherapy due to radiation-induced fibrosis with resultant alteration of the normal lymphatic flow [85, 236].

16.13 Thoracentesis Thoracentesis may carry an increased risk for patients with HM because of the presence of numerous comorbidities in these patients, neutropenia and coagulation

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abnormalities. Unfortunately, published data on the safety of the thoracentesis on this group of patients are sparse. Bass et  al. [17] retrospectively studied 100 (55 males/45 females) patients diagnosed with HM on whom a thoracentesis was performed (ultrasound localization was used in 32% of all cases). Lymphoma was present in 52% of them (46 with non-Hodgkin’s lymphoma and 6 with HD), whereas 9 patients were diagnosed with acute myeloid leukemia, 7 with MM, 6 with CLL, 2 with acute lymphocytic leukemia, 1 with CML and 2 with amyloidosis. Bone marrow or stem cell transplants had been performed in 21% of patients, including 14 allogeneic transplants and 7 autologous transplants. The main indications for thoracentesis were exclusion of infection and documentation or diagnosis of malignancy. At the time of the thoracentesis, neutropenia was observed in 11 patients, a platelet count of <50,000 cells/mL in 13 patients, and coagulopathy with prothrombin time of >15  s and/or a partially activated thromboplastin time of >40 s was present in 14 patients in this study. Prior to the pleural fluid tap, platelet transfusions were performed in 18% of cases, and fresh-frozen plasma was administered in 7% of cases. Despite possible thrombocytopenia and coagulation defects, complications related to bleeding occurred in only two cases of the study (2%) resulting in hemothorax. Nevertheless, in both cases, no clearly identified coagulation defects were detected (platelet counts and coagulation study findings were normal; one patient though, had an elevated creatinine level of 2.0 mg/dL). Pneumothorax was also reported in 7% of patients, a rate comparable to that of nonimmunocompromised patients [57, 210], and a tube thoracostomy was required in 4% of patients. In general, all complications were successfully treated. The evaluation of safety of thoracentesis was the aim of another retrospective study in 50 hematopoietic stem cell transplantation (HSCT) recipients [3]. Of them, 26 patients underwent allogeneic HSCT, while 24 underwent autologous HSCT. Thirty-two patients (68%) in the study had underlying HM, while 17 patients (34%) had solid tumors. The main indications for performing thoracentesis were to exclude infection and document or diagnose malignancy. Before the procedure a platelet transfusion was given if the platelet count was below 50,000 cells/mm3, and fresh frozen plasma was given if the INR was more than 1.5. The

16  Pleural Effusions and Thoracentesis in Patients with Hematological Malignancies

only documented complication was pneumothorax in five patients; three were patients who had the procedure under radiological guidance. A tube thoracostomy was required in 4% of patients. None of the patients developed bleeding or hemothorax secondary to the thoracentesis. In another report [69] on 22 children with cancer and neutropenia (absolute neutrophil count, <1,500 per mm3), thoracentesis during febrile episodes in 22 patients revealed infection in 2 patients (9%), both of which were of fungal origin. Eight of the remaining nineteen patients underwent another diagnostic procedure, yielding five additional diagnoses. The procedure was performed with no complications. The authors conclude that thoracentesis is safe and should be considered as a diagnostic test for febrile neutropenic children with pulmonary effusions of presumed infectious etiology, although more invasive tests may be warranted. In conclusion, thoracentesis seems to be a simple, safe and well-tolerated procedure in patients with HM, with a complication rate that is similar to that reported in other patient populations, either immunocompromised or non-immunocompromised.

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Diagnostic Yield of BAL Fluid Cytology in Hematologic Malignancies

17

Jean-François Bernaudin and Jocelyne Fleury-Feith

Contents 17.1 Bronchoalveolar Lavage Cytology: Main Technical Points............................................ 210 17.1.1 Routine Cytology...................................................... 210 17.1.2 Electron Microscopy................................................. 210 17.1.3 Histochemical and Immunohistochemical Analysis.................................................................... 210 17.1.4 Flow Cytometry........................................................ 210 17.1.5 Molecular Biology Cell Analysis.............................. 211 17.2 Pulmonary Diseases in Which BAL Cytology is Diagnostic............................................ 211 17.2.1 BAL Cytology and the Diagnosis of Pulmonary Infectious Disease..................................................... 211 17.2.2 BAL and Diagnosis of Pulmonary Hemorrhage....... 213 17.2.3 BAL and Diagnosis of Secondary Alveolar Proteinosis.................................................. 213 17.2.4 BAL and Diagnosis of Pulmonary Lymphoma......... 215 17.3 Even When BAL Cytology Is Not Definitely Diagnostic, It Can Provide Valuable Clues......................................................... 217 17.3.1 Detection of Hematologic Malignant Cells in BAL in Leukemia.............................................................. 217 17.3.2 Other Malignant and Atypical Epithelial Cells in BAL Fluid.................................................... 218 17.3.3 Drug-Induced Lung Toxicity.................................... 218 17.3.4 Miscellaneous Situations.......................................... 219 17.4 Conclusion............................................................... 219 References............................................................................ 220

J.-F. Bernaudin (*) and J. Fleury-Feith  Cytopathology Unit, Laboratoire d’Histologie Biologie Tumorale, Université Pierre et Marie Curie Paris 6, Hôpital Tenon APHP, 75020, Paris, France e-mail: [email protected]; [email protected]

The lung is one of the most severely affected organs in the course of hematologic malignancies as a result of infection, specific localizations, drug-induced and radiation-induced damage, and pulmonary graft-versus-host disease [59, 67]. As this chapter is specifically devoted to the diagnostic value of analysis of the cells collected by bronchoalveolar lavage (BAL), detection of infectious agents will not be considered apart from certain characteristic cytopathogenic effects related to viral infections. The lung is a complex organ that can be divided into at least seven compartments [70], and BAL only provides access to the most readily accessible compartment, the bronchoalveolar space. Although BAL has been demonstrated to be very useful for clinical diagnosis, a number of questions remain unresolved on how these cells reflect the pathophysiology of other lung compartments. The use of BAL to investigate the alveolar component of the patient’s lung has been widely developed since the mid 1970s [63], and in one of the most frequently cited papers on BAL, published more than 30 years ago, the authors stated that “Over the past 10  years, these techniques have allowed enormous insight into how the human pulmonary inflammatory and immune systems function both in health and disease” [35]. During the 20 years between 1980 and 2000, a very large number of studies reported the value of BAL in the management of various pulmonary diseases, particularly those observed in immunocompromised patients or patients with hematologic malignancies. All data obtained by BAL together with a better understanding of the clinical and radiological features of pulmonary complications associated with hematologic malignancies and the various situations potentially encountered in the everyday care of patients are now fairly well known. According to various hematologists the need for diagnostic BAL is considered to have decreased over the last 10  years. Moreover, with the

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routine use of prophylaxis, the spectrum of pulmonary complications has evolved, and the value of bronchoscopy is now more controversial [55]. A major question in 2010 is therefore what is the real value of BAL in everyday management of these patients? In contrast with the recent report by [61] entitled “Is BAL useful in patients with acute myeloid leukemia admitted in ICU for severe respiratory complications?,” which concluded that patients with leukemia and lymphoma derived limited benefit from this procedure, we would like to discuss the various areas in which cytological examination of BAL fluid remains a particularly useful diagnostic tool in these patients. As an overview to this chapter, it should be noted that the diagnosis of pulmonary diseases associated with hematologic malignancies, such as pulmonary hemorrhage and pulmonary alveolar proteinosis, is based on BAL analysis not requiring pathologic examination of tissue samples. In primary lung lymphomas, BAL cytology is a particularly valuable first-line diagnostic procedure, and, in other situations, BAL cytology may make a major contribution to the diagnostic decision.

17.1 Bronchoalveolar Lavage Cytology: Main Technical Points

J.-F. Bernaudin and J. Fleury-Feith

count (macrophages, lymphocytes, neutrophils, eosinophils and mast cells) is obtained by counting at least 200 random cells. A normal BAL cell count is about 130 ± 20 103 mL−1 cells in non-smokers and 420 ± 50 103  mL−1 cells in smokers. The normal cell distribution is: lymphocytes 15 ± 3% (CD3+ T cells >95% with a CD4/CD8 ratio »2.5; CD19+ B cells <2%) neutrophils <3% and eosinophils <1%. However, the cell distribution observed on BAL is a snapshot of the intraalveolar cellular milieu, and when interpreting an unusual cell distribution, e.g. lymphocytes, the cytologist must bear in mind that increased numbers of cells in BAL fluid could be due to increased influx, increased local proliferation, reduced apoptosis or decreased efflux or even a combination of all these parameters [51].

17.1.2 Electron Microscopy For ultrastructural study, a 20-mL aliquot of fresh BAL fluid is immediately fixed in an equal volume of 2.5% glutaraldehyde in 0.1  M cacodylate buffer for 1  h at 4°C. The pellet is then collected by centrifugation (1,500 rpm for 10 min) and processed for transmission electron microscopy as usual [6].

17.1.1 Routine Cytology 17.1.3 Histochemical and Immunohistochemical Analysis BAL fluid is usually collected by fiberoptic bronchoscopy after instillation of 3 × 50 mL of saline solution kept at 4°C. The cytologist must take the ratio of recovered-to-instilled fluid into account to assess the significance of the results obtained. In addition to the samples sent to the cytology laboratory, other fluid aliquots are also systematically sent for bacteriologic, virologic and fungal cultures. The first step of the cell analysis procedure is a cell count usually using a hemocytometer grid, then centrifugation (1,200  rpm for 10  min) to obtain a 106  mL−1 cell concentration. Simple smears and cytospin preparations are obtained [in our practice, at least 4–6 cytospin preparations (100 mL of the 106 mL−1 cell suspension) are prepared by using a Cytospin Shandon Instrument (500 rpm for 10  min)]. After air-drying, the smears are stained by the May-Grunwald-Giemsa method (other staining methods may be used, such as Papanicolaou’s or Diff Quick stain to obtain rapid results). A differential cell

A smear is systematically stained by Perls’ method to detect hemosiderin-laden macrophages. Other histochemical stains may also be useful, such as PeriodicAcid Schiff reaction and Alcian blue for extracellular deposits (see: alveolar proteinosis) or oil red O for intra-macrophage lipid deposits. Immunocytochemistry that used to be performed on simple smears or cytospin preparations for lymphocyte subtyping has now been replaced by flow cytometry analysis.

17.1.4 Flow Cytometry Flow cytometry is essential for determination of lymphocyte subpopulations. Aliquots of 5 × 106  mL−1 cell

17  Diagnostic Yield of BAL Fluid Cytology in Hematologic Malignancies

suspension are directly incubated with anti-CD45, antiCD3, anti-CD4 and anti-CD8 for T cells, and anti-CD19 (and/or anti-CD79a) for B cells. In the case of an increase of the CD19-positive cell population or in the presence of lymphoplasmacytic cells or atypical lymphoid cells, BAL cells may be incubated with anti-k and anti-l light chain monoclonal antibodies using either the membranous or intracellular staining procedure. Systematic labeling using isotypic controls is performed. Lymphocyte subsets are determined by flow cytometry. Cytometric analysis of BAL cells using standardized procedures with optimum antibody concentrations and gating strategies has been clearly demonstrated to be correlated with immunocytochemical staining [54, 69]. This technique using commercially available antibodies offers a particularly reproducible and less time-consuming method than immunocytochemistry “on slides,” with access to a wide range of labeled monoclonal antibodies and using a three- or four-color cytometer.

17.1.5 Molecular Biology Cell Analysis Most reports concerning molecular biology analysis of BAL cells in hematologic malignancies have concerned the detection of monoclonal populations of B lymphocyte in lymphomas [77] based on the detection of rearrangements of genes encoding the B-cell immunoglobulin receptor using polymerase chain reaction (PCR). For this purpose, fresh or frozen cells are transferred to the molecular biology laboratory for DNA extraction and PCR analysis [56, 77].

17.2 Pulmonary Diseases in Which BAL Cytology is Diagnostic 17.2.1 BAL Cytology and the Diagnosis of Pulmonary Infectious Disease BAL has been clearly demonstrated to be useful for the diagnosis of pulmonary infectious complications occurring in patients with hematologic malignancies [15,34,48], but should BAL samples still be sent to the cytopathology unit or only to micro­ biology laboratories?

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As discussed in the various chapters of this book, pulmonary opacities in these patients can be due to a wide range of causes, in which BAL can be useful for diagnosis. Characteristic cytopathogenic effects are diagnostic for cytomegalovirus infection (Fig.  17.1) [15,16], and the cellular pattern also provides additional information on detection of the infectious agent itself, as in the case of Pneumocystis carinii (PCP) infection (Fig. 17.1). Acute hypoxemic respiratory failure in patients with chronic lymphoproliferative disease after bone marrow transplantation or chemotherapy should be considered to denote Pneumocystis pneumonia until proven otherwise [5]. BAL has been shown to be diagnostic in HIVnegative patients by detecting PCC in 78–87% of patients [9,52]. While in HIV-positive patients PCP is associated with numerous cysts and trophozoites observed on MGG-stained smears, in patients with hematologic malignancies only a few cysts are usually observed, which could make the diagnosis more difficult. Cytologic analysis comparing BAL in HIVnegative and HIV-positive patients with PCP [50] showed no difference for neutrophils, while eosinophils and lymphocytosis >15% were observed significantly more frequently in BAL specimens from HIV-positive patients [28]. However, in BAL from HIV-negative patients, PCP is characterized by lymphocytosis associated with lymphoplasmacytic cell proliferation [27]. Therefore, in the presence of an increase in alveolar lymphocytes associated with a lymphoplasmacytic proliferation, MGG or GomoriGrocott stained smears must be examined very meticulously to detect rare cysts. The presence of large numbers of neutrophils is highly suggestive of bacterial infection. Careful examination looking for intracellular bacteria is very important, as it has been demonstrated that the percentage of BAL cells containing intracellular bacteria in nosocomial pneumonia is closely correlated with the total number of bacteria obtained from corresponding lung samples [12] (Fig. 17.1). However, in neutropenic patients, severe neutropenia can be concomitant with decreased cellularity of the alveolar space, particularly affecting alveolar macrophages and neutrophils, and pulmonary bacterial infection may therefore not be associated with an increased number of alveolar neutrophils in BAL fluid [18].

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Fig. 17.1  Photographs of cysts of Pneumocystis carinii (a, b), intranuclear and intracytoplasmic inclusions characteristic of CMV infection (c), neutrophils containing intracellular bacteria (arrows) (d), erythrophagocytosis (arrow) observed within alve-

J.-F. Bernaudin and J. Fleury-Feith

olar macrophages (e) and siderophages stained blue by the Perls’ reaction (f) (Staining method: a, c–e: May–Grunwald–Giemsa; b: Grocott; f: Perls)

17  Diagnostic Yield of BAL Fluid Cytology in Hematologic Malignancies

17.2.2 BAL and Diagnosis of Pulmonary Hemorrhage Pulmonary hemorrhage is a frequent event in patients with hematologic malignancies due to infections as well as blood coagulation disorders [33] or after hematopoietic stem cell transplantation [2, 3, 15]. Diffuse alveolar hemorrhage is the paradigm of the diagnostic value of BAL. Alveolar hemorrhage can be diagnosed by progressively bloodier returns, but the presence of red blood cells in BAL fluid can be related to instrumental trauma, as most of these patients present clotting disorders (thrombocytopenia, etc.), and the appearance of the BAL return is not reliable for diagnosis [2]. The hallmark of alveolar hemorrhage is the presence of siderophages. Siderophages are alveolar macrophages that have phagocytosed red blood cells and digested them in their lysosomal compartment. The remnants of these red blood cells are intracytoplasmic deposits of hemosiderin, which stains dark blue by Prussian blue during Perls’ reaction using the ferrocyanide reagent (Fig. 17.1). It may take 33–72 h after acute alveolar hemorrhage for hemosiderin-laden macrophages, i.e., siderophages, to appear in BAL and at least 2–4 weeks for siderophages to clear from the lung and airways [68]. Due to the delayed appearance of siderophages, the absence of Perls’ positive siderophages in the BAL fluid does not exclude the possibility of recent (less than 33–48 h) alveolar bleeding (or old bleeding more than 12  days previously, as hemosiderin is cleared after a few days) [68, 3]. When alveolar hemorrhage is strongly suspected on bloody returns of BAL without siderophages, bronchoscopy repeated several days later might show the presence of siderophages [3]. However, if the BAL fluid kept at 4°C has been rapidly sent to the cytopathology unit, the observation of erythrophagocytosis by alveolar macrophages is a valuable criterion for recent intraalveolar bleeding (Fig. 17.1). Golde DW et al. [30] introduced a ranking score evaluating the hemosiderin load in alveolar macrophages. After staining cytospin preparations for hemosiderin, 200–300 macrophages were counted, and each cell was graded for hemosiderin on a scale from 0 to 4 (0 = no blue color; 1 = faint blue staining of the cytoplasm; 2 = dense blue color in a minor portion of cytoplasm or medium color intensity throughout the

213

cell; 3 = dark blue color in most of the cytoplasm; 4 = dark blue throughout the cytoplasm). A mean score, i.e., the Golde score, for 100 cells was calculated, where zero is the minimum score and 400 is the maximum score. In the initial publication [30], BAL from seven healthy volunteers was used as control, and the observed score was 11 ± 14 (SE). Hemosiderin resorption was therefore considered to be normal when the Golde score ranged from 0 to 20. The presence of alveolar hemorrhage was considered when the score was situated in the medium range from 20 to 70, and therefore associated with so-called occult alveolar hemorrhage, and a score >70 [30] or >100 [37] was highly significant of obvious alveolar hemorrhage. The Golde score has been used to identify pulmonary hemorrhage in various clinical contexts, such as leukemia [30], immunocompromised hosts [37] or pulmonary venoocclusive disease [62]. More recently, we, as well as other authors [2, 3, 22] have used the presence of 20% or more hemosiderinladen macrophages as the diagnostic criterion for diffuse alveolar hemorrhage. To obtain such a criterion the Golde score was compared to the percentage of siderophages stained by Prussian blue counted on at least 200 macrophages in 47 BALs from immunocompromised patients [22]. A percentage of siderophages between 20% and 67% was correlated with a Golde score between 20 and 100 and was classified as intermediate by [37], whereas a percentage of siderophages greater than 67% was correlated with a Golde score greater than 100 and was classified as severe by [37]. In normal individuals, the percentage of siderophages was always less than 10% [22]. A percentage of siderophages within the alveolar macrophage population greater than 20% is therefore significant for the presence of alveolar hemorrhage. This method is simpler and faster than the Golde score to establish the diagnosis [2, 3].

17.2.3 BAL and Diagnosis of Secondary Alveolar Proteinosis Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by deposition in the air spaces of a granular extracellular material composed of proteins and lipids [24]. Secondary PAP develops in association with conditions involving functional impairment or

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reduced numbers of alveolar macrophages and/or type II pneumocytes, as in some hematologic malignancies [72]. It is associated with different hematologic malignancies particularly acute and chronic myeloid leukemia [16, 17, 36, 53, 67, 71]. PAP is a good example of a lung disease in which BAL is useful for early diagnosis and treatment [17]. Bronchoalveolar lavage fluid in patients with PAP has an opaque and/or milky appearance. Alveolar macrophages are rare and often have a large and foamy, “destroyed” appearance associated with either

lymphocytes or neutrophils [17]. In some samples, the differential cell count may not be feasible due to the abundance of extracellular material. The extracellular deposits are the hallmark of the disease and are composed of large acellular bodies in a diffuse background of granules faintly stained by the May-Grunwald or Papanicolaou methods (Fig. 17.2). This proteinaceous material exhibits periodic-acid Schiff (PAS) staining (Fig.  17.2) with no significant Alcian blue staining except when small areas of bronchial mucus are intermixed [43].

Fig.  17.2  Characteristic features of pulmonary teinosis: acellular material (star) faintly stained Grunwald–Giemsa method (a) pink-red after Schiff (PAS) staining (b). Electron microscopy

extracellular material composed of a mixture of electron-dense material and osmiophilic figures (c, d). Insert in d shows the characteristic tubular myelin

alveolar proby the May– periodic-acid examination:

17  Diagnostic Yield of BAL Fluid Cytology in Hematologic Malignancies

On electron microscopy examination, the extracellular material is composed of a mixture of electrondense granular or amorphous material, osmiophilic amorphous droplets, and regular and concentric myelin-like laminated figures (Fig.  17.2) associated with tubular myelin (Fig. 17.2) characteristic of lipoprotein aggregates and diagnostic of PAP [20]. Ultrastructural studies show that alveolar macrophages contain giant secondary lysosomes filled with the same material that accumulates within the alveoli [31].

17.2.4 BAL and Diagnosis of Pulmonary Lymphoma In contrast with some authors who have reported that “BAL and bronchial brushings were never diagnostic” in a series of 28 patients with pulmonary AIDSrelated non-Hodgkin’s lymphoma [25], BAL is a particularly informative investigation that may contribute to the diagnosis of either primary or secondary malignant lymphoproliferative disorders of the lung. For example, a 67% diagnostic yield of BAL has been reported in non-Hodgkin’s lymphoma (NHL) [60, 66]. However, the diagnostic yield is particularly good in primary B-cell lymphoma or mucosa-associated lymphoid tissue (MALT) type, but is low in Hodgkin’s disease [60]. Lymphomas may involve the lung parenchyma in three ways: (1) hematogenous dissemination of nonHodgkin’s lymphoma or Hodgkin’s disease, (2) contiguous invasion from hilar or nodal lymphoma or (3) primary pulmonary involvement [10]. Two different situations may be encountered: firstly, BAL performed to investigate chronic pulmonary opacities suggesting a wide range of diagnoses, particularly primary pulmonary lymphoma [23, 10]; secondly, BAL performed to investigate pulmonary opacities occurring during the course of a known ­lymphoma, Hodgkin’s disease or non-Hodgkin’s lymphoma.

17.2.4.1 Primary Pulmonary Lymphoma Primary pulmonary lymphomas are rare events, re­presenting 3–4% of all extranodal non-Hodgkin’s

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lymphomas, including: (1) low-grade-B cell primary pulmonary lymphoma (PPL-B), the most frequent form (58–87%); (2) high-grade PPL-B and lymphomatoid granulomatosis, a particularly rare disorder [10]. MALT (mucosa-associated lymphoid tissue) lymphomas represent 90% of PPL-B. There is a consensus that it is important to obtain representative tissue for histologic evaluation and classification of lymphomas, but it can be very difficult to obtain such samples. By showing typical lymphomatous cells or a clonal restricted population of lymphocytes, BAL is therefore very useful in this situation. In a series of 13 patients with lymphoma, BAL showed lymphocytosis in every case [23], and, in a more recent study of 20 patients, the mean lymphocytosis in primary and secondary lymphoma was 30% and 36%, respectively (Table 17.1) [77]. BAL is particularly useful in these patients when it shows lymphocytic alveolitis (lymphocytes >20% of total cells) (Fig. 17.3) mainly composed of T lymphocytes [23], but including at least 8–10% of B-lymphocytes [10, 14, 19, 49, 77]. The detection of abnormal lymphoid cells may also be diagnostic (Fig. 17.3). These cells are inconstantly detected [8, 39, 56, 58, 59], whereas in the series by Poletti (1995) [59], 67% of 15 cases of NHL and 3 of the 9 cases of Hodgkin’s lymphoma were identified by the presence of characteristic cells, and, in a recent series, they were observed in 9 out of 20 patients (45%) with pulmonary B-NHL [77]. In indolent B-cell lymphoma, lymphomatous cells may have morphological features that do not differ from those of

Table 17.1  Results of BAL cytology in 20 cases of pulmonary non-Hodgkin’s lymphoma Secondary Primary pulmonary pulmonary NHL (n = 8) NHL (n = 12) % lymphocytes mean (range)

36 (3–81)

30 (3–61)

Samples with abnormal cells

6

3

Lymphocyte phenotypes n samples studied CD3% (range) CD4% (range) CD8% (range) CD19% (range)

7

2

58 (27–90) 35 (11–77) 23 (8–56) 37 (9–62)

98–79 28–21 71–24 0–18

Modified according to [77]

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J.-F. Bernaudin and J. Fleury-Feith

a

b

c

d

CD19

2

104 103

Anti-Lambda PE-A

Q2-1

Q3-1

Q3-1 102

Q4-1

-293

10

Q1-1

0

Q4-1

CD19 105

Q2-1

104

Q1-1

f

103

Anti-Lambda PE-A

105

e

103 104 Anti-Kappa FITC-A

105

Fig. 17.3  Photographs of normal (a) and atypical lymphoplasmacytoid lymphocytes (b) and abnormal lymphoid cells from pulmonary non-Hodgkin lymphoma (c, d) mixed with red blood cells and alveolar macrophages (Staining: May-GrunwaldGiemsa method). Example of flow cytometry analysis of immu-

102

103

104

105

Anti-Kappa FITC-A

noglobulin light chain expression gated on alveolar CD19 lymphocytes (top of e and f) showing a normal distribution of k and l light chains (e) and a k light chain restriction demonstrating a B-cell monoclonality (f)

17  Diagnostic Yield of BAL Fluid Cytology in Hematologic Malignancies

normal (Fig.  17.3) or “activated” lymphocytes. Atypical lymphocytes with nuclear membrane irregularities and indentations or lymphoplasmacytoid lymphocytes may be observed, and their presence is suggestive of the diagnosis (Fig.  17.3). As already emphasized, these same morphological features may also be present in non-malignant lymphoproliferative disorders, such as lymphocytic interstitial pneumonia or diffuse Castelman’s disease [60]. In high-grade B cell lymphoma, characteristic malignant cells (large cleaved and non-cleaved cells) are suggestive of the diagnosis [60]. As lymphocytes can spread from the lung parenchyma to the alveolar air spaces, the lymphocyte repertoire recovered by BAL reflects the pulmonary infiltration repertoire, and it has been demonstrated that the same dominant B-cell clone is detected in BAL fluid and in lung biopsies of lymphoma [8, 39, 56, 77]. Demonstration of B-cell monoclonality is mandatory for a precise diagnostic report. B-cell monoclonality is demonstrated by immunocytochemistry or flow cytometry assessment of immunoglobulin light chain restriction [39, 49, 58] (Fig.  17.3). Gene rearrangement analysis, i.e., Ig gene clonal rearrangements, using molecular biology, initially Southern blotting, but now usually polymerase chain reaction (PCR) [8, 39, 56, 77], can confirm the results obtained by flow cytometry assessment of immunoglobulin light chain restriction. Zompi S et al. [77] demonstrated the feasibility of clonality analysis of BAL cells by complementary molecular analysis of lymphocytes in routine practice based on the detection of rearrangements of the gene encoding the B-cell immunoglobulin receptor using PCR [77]. In a series of 106 patients with clinical suspicion of pulmonary NHL, the detection of a strong B-cell clonal population within the BAL cell population was associated with the diagnosis of pulmonary NHL (p < 0.0001) with 97% specificity and 95% negative predictive value [77]. However, they noticed that a minor benign B-cell clone can also be detected, particularly in autoimmune and chronic infectious diseases, but its predictive value for the subsequent development of lymphoma remains unclear [77]. A similar approach has been used for pulmonary sites of T-cell CD3−/CD8+ lymphoma by analy­ zing the clonal rearrangement of the T-cell receptor [39].

217

17.2.4.2 Other Lymphomas and Hodgkin’s Disease Reports on BAL cytology and the diagnosis of other types of pulmonary lymphomas are rare. BAL may be appropriate for investigating pulmonary parenchymal involvement in Hodgkin’s disease, as Reed-Sternberg cells may be observed in BAL [26,74], but reactive large lymphoid cells must not be mistaken for ReedSternberg cells, which must meet  all of the classical diagnostic criteria. The diagnostic yield of BAL for the diagnosis of Hodgkin’s lymphoma seems to be low (33% in [66]), but no large series has been published. Diffuse myelomatous pulmonary infiltration may be diagnosed by BAL in the presence of monoclonal plasma cells [38].

17.3 Even When BAL Cytology Is Not Definitely Diagnostic, It Can Provide Valuable Clues 17.3.1 Detection of Hematologic Malignant Cells in BAL in Leukemia Pulmonary leukemic cell infiltrates are found at autopsy in 31–66% of patients dying from leukemia [33], but symptomatic leukemic infiltration of the lung is the least common cause of pulmonary infiltrates [4,60]. However, BAL detection of malignant cells has been reported to be very valuable for the diagnosis of specific pulmonary infiltration, particularly in acute monocytic leukemia [4,65]. Rossi et  al. [65] first reported the detection of 20% of monoblastic cells in the BAL of a patient with monocytic leukemia. Azoulay et al. [4] subsequently reported a series of 20 patients admitted for acute respiratory failure due to acute monocytic leukemia and detected monoblastic cells in four cases (20%). The presence of blast cells in BAL fluid may be difficult to interpret when the peripheral blood blast cell count is particularly high, as BAL fluid may be contaminated by peripheral blood cells [4]. When a pulmonary site of a chronic lymphoid leukemia is suspected, similar rearrangements of the gene encoding the B-cell Ig receptor should be observed in BAL and blood lymphocytes, but as these patients

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usually have a high blood lymphocyte count, the results must be interpreted cautiously. Reports of the contribution of BAL to the diagnosis of pulmonary leukemic infiltration can therefore be considered to be anecdotal [60].

J.-F. Bernaudin and J. Fleury-Feith

specimens: recent cytoreductive treatment, positive bacterial cultures or graft-versus-host disease [32]. Reactive type II pneumocytes, large cells with a large round nucleus and a dark blue stained cytoplasm after MGG staining, are frequently observed in the case of alveolar damage [60].

17.3.2 Other Malignant and Atypical Epithelial Cells in BAL Fluid

17.3.3 Drug-Induced Lung Toxicity

Lung cancer may occur in patients with hematologic malignancies, as lung cancer is one of the two most common solid tumors occurring after Hodgkin’s disease [1,41] and has been the subject of recent reports after non-Hodgkin’s lymphoma (NHL) [21,46,47]. Bronchioloalveolar carcinomas have been rarely reported after treatment for Hodgkin’s disease [40] or leukemia, particularly with busulfan [13,45]. It is now widely recognized that BAL cytology provides a major contribution to the diagnosis of peripheral lung carcinoma, particularly adenocarcinomas with a pneumonic pattern in which a diagnostic yield of 66% has been reported [75]. However, numerous non-neoplastic lung diseases may be associated with atypical cells in BAL specimens, raising diagnostic challenges with malignant neoplasms [57, 60]. Atypical cells may be seen as single cells or in clusters mimicking cells desquamating from bronchioloalveolar carcinomas (Fig.  17.4). Bone marrow transplant (BMT) recipients have many predisposing factors to the presence of atypical cells in BAL

In hematologic patients with acute hypoxemic respiratory failure, BAL is considered to be essential, first to rule out an opportunistic infection, but also to look for evidence of drug-related toxicity [5,11]. The various patterns of infiltrative drug-induced respiratory diseases were reviewed in a recent exhaustive review by Camus P et al. [11]. In nonspecific interstitial pneumonia (NSIP) (caused by methotrexate in the majority of cases, or azathioprine, chlorambucil, cyclophosphamide and rarely vinca alkaloids), BAL fluid usually shows a lymphocytic infiltration. CD4+ and CD8+ lymphocytes have both been shown to contribute to alveolitis [29]. A low CD4+/CD8+ ratio of alveolar lymphocytes is suggestive, but not diagnostic for drug-induced lung disease [11]. Recently pulmonary drug reaction induced by dasatinib treatment for chronic myeloid leukemia has been reported with lymphocytic (25–92%) alveolitis and a CD4/CD8 ratio between 2.9 and 4.8 [7]. Another pattern, consisting of T-cell lymphocytic alveolitis associated with scattered eosinophils, is

Fig. 17.4  Photographs of alveolar non-malignant atypical cells (a) and clusters of malignant cells from bronchioloalveolar carcinoma (b). (Staining: May–Grunwald–Giemsa method)

17  Diagnostic Yield of BAL Fluid Cytology in Hematologic Malignancies

highly suggestive of drug-induced lung damage as observed for methotrexate [59]. True pulmonary eosinophilic pneumonia is rarely observed as an adverse drug reaction in patients with hematologic diseases in contrast with patients in other settings where many drugs may induce this pattern of lung reaction [11]. Organizing pneumonia is a distinctive lung response; increased numbers of lymphocytes, neutrophils or eosinophils may be observed, but there is no distinctive BAL pattern.

17.3.4 Miscellaneous Situations Acute non-infectious eosinophilic pneumonia not related to adverse drug reaction has been reported after stem cell transplantation [73,76]. The association of alveolar lymphocytosis and GVHD is well known, but the pathogenesis of pulmonary GVHD is still poorly understood. In a mouse model, the acute phase of GVHD appears to be mediated by CD8+ cells, whereas CD4+ cells are associated with the chronic form [60]. However, in patients, late onset of interstitial pneumonitis

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following allogeneic bone marrow transplantation has been associated with lymphocytic alveolitis with an overall expansion of the CD8+ subset [42]. More recently, a study on BAL fluid cell composition in pediatric bone marrow transplant (BMT) recipients with pulmonary GVHD showed BAL lymphocytosis associated with severe epithelial cell atypia. The authors concluded that this pattern “may suggest the diagnosis” of pulmonary GVHD, but is not diagnostic per se [64]. Other lung diseases not directly associated with hematologic malignancies may be present in these patients. For example, as an illustration of the value of systematic immunophenotyping of lymphocytes, sarcoidosis was demonstrated in a patient with chronic lymphocytic leukemia due to the predominance of CD4+ T cells instead of B lymphocytes in BAL fluid [44].

17.4 Conclusion The various “cytological” situations most frequently encountered are summarized in Table 17.2.

Table 17.2  Summary of the more frequent “cytological” situations encountered in BAL cytology in hematologic patients Cytology Complementary investigation Diagnosis Siderophages >20%

None

Alveolar hemorrhage

Abundant extracellular material

PAS; Alcian blue

Secondary PAP

Abnormal cells   Lymphoid   Myeloid   Epithelial

Immunotyping and genotyping

NHL or Hodgkin’s leukemia benign or malignant atypical cells

Immunotyping (TTF1) and molecular biology (Ras, EGFR mutations)

Lymphocytosis CD4 and/or CD8 T lymphocytes, B lymphocytes >8%

Light chain clonality and IgR rearrangement

Adverse drug reaction, B-cell lymphoma; CLL

Neutrophils >+++

Intracellular bacteria

Bacterial infection; ARDS

Eosinophils >++

Adverse drug reaction

220 Acknowledgments  The authors would like to thank MarieJosé Pocholle, Christine Carre, (Unité de Cytopathologie Hôpital Henri Mondor Créteil France), Danièle Cesari, Claudie Prengel and Patricia Roynard (Unité de Cytopathologie Hôpital Tenon Paris France) for their excellent technical assistance in cytopathology and cytometry over all these years and Marie-Claire Pinchon † and Anne Marie Vojtek (Laboratoire de Microscopie Electronique CHIC Creteil France) for their valuable expertise in electron microscopy of BAL. They would also like to thank Catherine Cordonnier, MD, and Estelle Escudier, MD, from the Hematology Department of Hôpital Henri Mondor Créteil France, with whom we developed our work on BAL 25  years ago, and Anne Fajac, MD, who joined us more recently on this topic.

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48. Murray PV, O’Brien MER, Padhani AR et al (2001) Use of first line bronchoalveolar lavage in the immunosuppressed oncology patient. Bone Marrow Transplant 27: 967–971 49. Nehashi Y, Nakano M, Utsumi K et al (1993) Primary pulmonary B-cell lymphoma diagnosed by kappa-lambda imaging of broncho-alveolar lavage fluid lymphocytes. Intern Med 32:480–483, 0 50. Nüesch R, Bellini C, Zimmerli W (1999) Pneumocystis carinii pneumonia in human immunodeficiency virus (HIV)positive and (HIV)-negative immunocompromised patients. Clin Infect Dis 29:1519–1523 51. Pabst R, Tschernig T (1997) Lymphocyte dynamics: caution in interpreting BAL numbers. Thorax 52:1078–1080 52. Pagano L, Fianchi L, Mele L et al (2002) Pneumocystis carinii pneumonia in patients with malignant haematological diseases: 10 years’ experience of infection in GIMEMA centres. Br J Haematol 117:379–386 53. Pamuk GE, Turgut B, Vural O et al (2003) Pulmonary alveolar proteinosis in a patient with acute lymphoid leukaemia regression after G-CSF therapy. Leuk Lymphoma 44: 871–874 54. Papiris SA, Kollintza A, Kitsanta P et al (2005) Relationship of BAL and lung tissue CD4+ and CD8+ T lymphocytes and their ratio in idiopathic pulmonary fibrosis. Chest 128:2971–2977 55. Patel NR, Lee PS, Kim JH et  al (2005) The influence of diagnostic bronchoscopy on clinical outcomes comparing adult autologous and allogeneic bone marrow transplant. Chest 127:1388–1396 56. Philippe B, Delfau-Larue MH, Epardeau B et  al (1999) B-cell pulmonary lymphoma: gene rearrangement analysis of bronchoalveolar lymphocytes by polymerase chain reaction. Chest 115:1242–1247 57. Poletti V, Romagna M, Ka A et al (1995) Bronchoalveolar lavage in the diagnosis of disseminated lung tumors. Acta Cytol 39:472–477 58. Poletti V, Romagna M, Gasponi A et  al (1995) Bronchoalveolar lavage in the diagnosis of low-grade, MALT type, B-cell lymphoma of the lung. Monaldi Arch Chest Dis 50:191–194 59. Poletti V, Salvucci M, Zanchini R et al (2000) The lung as a target organ in patients with hematologic disorders. Haematologica 85:855–864 60. Poletti V, Poletti G, Murer B et al (2007) Bronchoalveolar lavage in malignancy. Semin Respir Crit Care Med 28: 534–545 61. Rabbat A, Chaoui D, Lefebvre A et al (2008) Is BAL useful in patients with acute myeloid leukemia admitted in ICU for severe respiratory complications? Leukemia 22:1361–1367 62. Rabiller A, Jaïs X, Hamid A et  al (2006) Occult alveolar haemorrhage in pulmonary veno-occlusive disease. Eur Respir J 27:108–113 63. Reynolds HY, Newball HH (1974) Analysis of proteins and respiratory cells obtained from human lungs by bronchoalveolar lavage. J Lab Clin Med 84:559–573 64. Rochat I, Posfay-Barbe KM, Kumar N et  al (2008) Bronchoalveolar cytology for diagnosing pulmonary GVHD after bone marrow transplant in children. Pediatr Pulmonol 43:697–702

222 65. Rossi GA, Balbi B, Risso M et al (1985) Acute myelomonocytic leukaemia: demonstration of pulmonary involvement by bronchoalveolar lavage. Chest 87:259–260 66. Semenzato G, Poletti V (1992) Bronchoalveolar lavage in lung cancer. Respiration 59:44–46 67. Sharma S, Nadrous HF, Peters SG et al (2005) Pulmonary complications in adult blood and marrow transplant recipients: autopsy findings. Chest 128:1385–1392 68. Sherman JM, Winnie G, Thomassen MJ et al (1984) Time course of hemosiderin production and clearance by human pulmonary macrophages. Chest 86:409–411 69. Smith PA, Kohli LM, Wood KL et  al (2006) Cytometric analysis of BAL T cells labelled with a standardized antibody cocktail correlates with immunohistochemical staining. Cytometry B Clin Cytom 70:170–178 70. Tschernig T, Pabst R (2009) What is the clinical relevance of different lung compartments? BMC Pulm Med 9:39 71. Tomonari A, Shirafuji N, Iseki T et al (2002) Acquired pulmonary alveolar proteinosis after umbilical cord blood transplantation for acute myeloid leukaemia. Am J Hematol 70: 154–157

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New Methods for Bacterial Diagnosis in Patients with Hematological Malignancies

18

Agnès Ferroni and Jean-Ralph Zahar

Contents

18.1 Introduction

18.1 Introduction............................................................. 223

Determining the etiology of pulmonary infiltrates in patients with hematological malignancies (HM) is challenging, and early empirical treatment with broadspectrum antimicrobial agents is therefore used when an infection is suspected, with the goal of improving patient outcomes. However, selection of the empirical antibiotics benefits considerably from the early identification of organisms such as Streptococcus pneumoniae, Haemophilus influenzae, nosocomial bacteria, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila, viruses, and fungi. Traditionally, the identification of causative bacteria rests on blood cultures: sputum cultures for common pathogens and M. tuberculosis; serological tests for C. pneumoniae, M. pneumoniae, and L. pneumophila; and cultures of specimens obtained using invasive techniques such as endoscopic bronchial aspiration or bronchoalveolar lavage (BAL). These methods are slow to produce results, lack sensitivity, and are influenced by previous antibiotic therapy. The diagnostic yield of BAL for identifying the cause of pulmonary infiltrates in patients with HM has varied between 31% and 49% [6, 28, 35, 36, 68, 85]. Thus, BAL has a limited impact on early therapeutic decisions. In recent years, noninvasive techniques such as L. pneumophila or S. pneumoniae antigen detection in urine have proved capable of providing the early etiological diagnosis of infections and, therefore, of allowing the early administration of appropriate antimicrobials. In addition, recent advances in molecular diagnostic technology, such as nucleic acid amplification (PCR), have improved the ability to rapidly identify the cause of pneumonia [46]. PCR detects minute amounts of nucleic acid from potentially all respiratory pathogens and is less affected by prior antimicrobial therapy than

18.2 PCR.......................................................................... 224 18.2.1 Specific PCRs in Respiratory Samples..................... 224 18.2.2 Specific PCR on Blood Samples.............................. 227 18.2.3 Universal PCR.......................................................... 228 18.3 Antigen Detection................................................... 228 18.3.1 Legionella................................................................. 228 18.3.2 Streptococcus pneumoniae....................................... 229 18.4 Conclusion............................................................... 230 References............................................................................ 231

A. Ferroni (*) and J.-R. Zahar Laboratoire de Microbiologie, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades and Université René Descartes Paris 5, Faculté de Médecine, 149 Rue de Sèvres, 75015 Paris, France e-mail: [email protected]

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_18, © Springer-Verlag Berlin Heidelberg 2011

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are culture-based methods [47]. PCR is probably more sensitive than most comparator culture-based diagnostic tests, as it is affected neither by decreased organism viability associated with specimen transportation nor by previous antibiotic therapy. It must be kept in mind that PCR does not differentiate between viable and nonviable bacteria and that there are no clear data in the literature on DNA decay after the end of antibiotic treatment. The use of antigen detection in clinical samples and recent advances in real-time amplification systems are discussed here with reference to respiratory bacteria known to cause pneumonia in patients with HM. Unlike the identification of viruses and fungi, for which these new methods have been evaluated in immunocompromised patients [25, 35, 51, 57, 87], the identification of bacteria has been mainly evaluated in patients with community-acquired infections. Table 18.1 lists the methods that can be used in immunocompromised patients with suspected pneumonia.

18.2 PCR PCR techniques play a major role in the diagnosis of infections that are either very difficult or impossible to diagnose rapidly by other methods. PCR is especially useful for detecting pathogens that are not known to colonize the human respiratory tract (e.g., Legionella species), as a positive result strongly suggests infection. To date, PCR methods have been developed for all the major pneumonia-causing pathogens, and commercial assays are available for some of them. However, few studies have compared different assays, and the techniques have not been standardized. PCR detection involves the extraction of bacterial DNA from the sample (nasopharyngeal aspirate, BAL, sputum, or throat swabs), followed by amplification using primers. Increasingly, real-time PCR techniques, based on fluorescent probes, are superseding the traditional PCR tests in which the products obtained at the end of the amplification cycles are revealed on agarose gel (end-point reaction). The main advantages of realtime PCR are rapidity; safety; ability to quantify bacterial DNA in the specimen; and, given that a single tube is used for all the steps, a reduced risk of crosscontamination.

A. Ferroni and J.-R. Zahar

Cases of culture-positive samples with negative PCR results may be due to DNA degradation, delayed assay performance, or presence of specific inhibitors. Samples, such as sputum or BAL, may include inhibitors, which can cause false-negative results. Therefore, an internal control coextracted with the clinical samples must be used to ensure accurate control of the entire assay [67]. PCR techniques target a single organism (simplex PCR), multiple organisms (multiplex PCR), or all organisms (universal PCR).

18.2.1 Specific PCRs in Respiratory Samples 18.2.1.1 Intracellular Bacteria Patients with suspected respiratory infections are generally evaluated using PCR tests that target specific organisms to diagnose atypical pneumonia or pneumonia due to fastidious organisms. These organisms are theoretically not found as commensals in the respiratory tract, and qualitative detection is therefore appropriate [79].

M. pneumoniae, C. pneumoniae M. pneumoniae can be cultured in a routine laboratory on acellular media, but the results are obtained only after 2–3 weeks, and the test is relatively insensitive [19]. C. pneumoniae can be cultured only on cell lines in specialized laboratories, which requires 5–10  days. As a result, the diagnosis of these two organisms relied until recently on serological tests, whose disadvantage is that they provide only a retrospective diagnosis. In addition, IgM antibodies to M. pneumoniae can persist for years, with levels remaining elevated in asymptomatic individuals [62], particularly healthy children. Furthermore, the variable specificity and sensitivity of current test kits influence the significance of the serological results [5]. Both organisms require treatment with macrolides, tetracyclines, or fluoroquinolones, and therefore sensitive, specific, and fast detection methods available in routine bacteriological practice would be valuable. Real-time PCR is being increasingly used

No

NE NE NE

No

No

No

No

No

No

PCR targeting atypical bacteria (M. pneumoniae, C. pneumoniae)

PCR targeting Legionella

PCR ARNr16S

Multiplex PCR

PCR targeting S. pneumoniae or H. influenzae

PCR targeting Mycobacteria

Yes

NE

NE

No

Yes

Yes

No

NE

NE (only quantitative PCR)

NE

NE (only onto sterile fluid)

Yes

Yes

NE

No

Yes

Yes

Yes

Yes

Yes

Yes

Pleural fluid

No

No

No

No

No

Yes

No

Throat swab

a

NE not evaluated in patients with hematological malignancies Time from DNA extraction to availability of the PCR result; however, in most laboratories, PCR and sequencing are not performed every day

NE

No

Yes

Yes

Antigen detection (S. pneumoniae or L. pneumophila 1)

Table 18.1  New bacterial diagnosis methods potentially applicable in patients with hematological malignancies Method Sample type Urine Serum Sputum Bronchoalveolar lavage fluid

3 h

3 h

3 h

4–8 h

3 h

3 h

10 min

Time-to-resulta

18  New Methods for Bacterial Diagnosis in Patients with Hematological Malignancies 225

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for the rapid diagnosis of these organisms [21, 22, 48]. Recently, PCR was found better than serology for confirming M. pneumoniae infection in the clinically important first week after pneumonia symptom onset [61]. Nevertheless, in case of late sampling or clearance of the organism following antibiotic treatment, PCR detection may be less sensitive than serology [37]. The targets most commonly used for M. pneumoniae are adhesin P1, 16S rRNA, and ATPase operon gene, and for C. pneumoniae, the outer membrane protein ompA and ARNr16S. These specific targets can be sought in samples contaminated with commensal flora such as sputum, potentially contaminated BAL, or throat swab containing cells or nasopharyngeal aspirates. Sputum samples have been shown to be more useful than upper respiratory tract samples for PCR identification of M. pneumoniae and C. pneumoniae [20, 69, 77]. The time-to-result varies across methods from 50 to 90 min. Commercial realtime PCR kits showed variable sensitivities, and their cost was five times higher than that of an in-house assay [81].

Legionella Legionella species are among the most underdiagnosed causes of pneumonia, due to the major shortcomings of existing diagnostic tests. Isolation of the organism is usually the preferred method but has several limitations, including fastidious growth requirements, extended incubation periods (3–10 days), and overgrowth by other bacteria. Direct L. pneumophila detection in clinical specimens by immunofluorescence methods is rapid but lacks sensitivity. Finally, soluble polysaccharide antigen detection in urine detects only L. pneumophila 1 [73]. PCR for rapid L.  pneumophila diagnosis, in contrast, detects all Legionella species [16, 32, 53, 70, 89]. The most frequently described Legionella PCR targets are the mip gene (macrophage infectivity potentiator), a virulence gene present in the majority of Legionella species, and the ADNr 5S gene. As Legionella does not colonize the human respiratory tract, the specific target genes can be sought in samples contaminated with commensal flora such as sputum or potentially contaminated BAL. PCR can now be considered the test of choice for legionellosis [59], but standardized protocols need to be developed.

A. Ferroni and J.-R. Zahar

18.2.1.2 Common Bacteria (S. pneumoniae, H. influenzae, Staphylococcus aureus, etc.) Pulmonary infections due to common bacteria are underdiagnosed because of the limitations of conventional diagnostic tests. Blood cultures lack sensitivity, particularly in patients who have received previous antibiotic treatment. Isolation of S. pneumoniae or H. influenzae from sputum or BAL may occur as a result of oropharyngeal contamination. Conversely, isolation may fail because of previous antibiotic therapy, poor transportation conditions, or small inoculum size. Recently, studies have been carried out on PCRs targeting pyogenic bacteria. However, these tests may be difficult to interpret, as pyogenic bacteria may be present in the commensal flora, making it difficult to distinguish between colonization and infection. These PCRs are therefore feasible in routine practice only on samples that do not contain pyogenic bacteria as commensals, such as pleural fluid or lung biopsies. Preliminary evaluations of PCR applied to pleural fluid indicate good sensitivity for the diagnosis of pneumococcal pneumonia [23, 47]. In theory, BAL fluid and sputum, which are often colonized by S. pneumoniae or H. influenzae, particularly in children, can be used only if cultures are negative. Nevertheless, a number of investigators have assumed that quantitative PCR may be useful for assessing these contaminated respiratory samples, as the bacterial burden is higher in infection than in colonization [40, 43]. The amount of target nucleic acid in the sample is inversely related to the cycle threshold (Ct) value. This relationship can be used to establish a Ct value cutoff that provides optimal sensitivity and specificity by preventing false-positive results due to colonization with small numbers of organisms. A panel of six real-time PCR assays, including the lytA gene of S. pneumoniae and the 16S rRNA genes of H. influenzae and S. pyogenes, were used by Morozumi et al. [56] in a study of 429 clinical samples (sputum, nasopharyngeal aspirates, or throat swabs) from children and adults with pneumonia. Sensitivity and specificity, compared to clinical specimen cultures, were as follows: 96.2% and 93.2% for S. pneumoniae, 95.8% and 95.4% for H. influenzae, and 100% and 100% for S. pyogenes. The Ct values of S. pneumoniae and H. influenzae showed excellent correlations with the semi-quantitative culture results. All patients with positive PCR and negative culture results for these two pathogens had a history of previous antibiotic therapy.

18  New Methods for Bacterial Diagnosis in Patients with Hematological Malignancies

Another controlled study evaluated the culture-PCR correlation in 235 adults with clinically and biologically confirmed pneumonia. In patients not treated with antibiotics, the PCR-culture correlation was good, whereas in treated patients, PCR improved the etiological diagnostic yield by 10%. However, in the control group, PCR performed on nasopharyngeal aspirates showed the presence of H. influenzae and S. pneumoniae in 5% and 8% of cases, respectively [78]. Recently, Kumar et  al. found S. pneumoniae and S. aureus in 14% and 8.5% of asymptomatic patients, respectively, underlining the poor specificity of PCR [46]. Specificity can be expected to increase in the near future with improvements in PCR result interpretation, including the determination of Ct cutoffs for quantitative PCR in various pulmonary samples and in well-defined patient populations. Another difficulty in interpreting PCR results stems from the specificity of the target genes used for pneumococcal PCR. The targets used in many pneumococcal PCR assays are the pneumolysin and autolysin genes, but recent evidence casts doubt on their specificity, as these genes, especially pneumolysin, may been found in closely related viridans group Streptococci [58, 84, 88]. Recently, the Spn9802 gene fragment compared favorably with quantitative lytAbased real-time PCR in distinguishing patients with pneumonia from control individuals [1].

18.2.1.3 Mycobacterium tuberculosis and Atypical Mycobacteria PCR tests perform well on M. tuberculosis smear-positive specimens but are less sensitive than culturing. Therefore, PCR is recommended only for smear-positive samples, to determine the species without waiting for the culture result. However, in a study involving routine M. tuberculosis PCR in patients with HM, M.  tuberculosis was found in 2/128 BAL specimens negative by microscopy, which considerably shortened the time to diagnosis [35]. The M. tuberculosis PCR uses two main targets: a specific portion of the 16S RNA gene and the insertion sequence IS6110. In recent years, real-time PCR techniques have increasingly superseded conventional PCR [11, 24, 66]. Until recently, very few commercial M. tuberculosis PCR kits were available, whereas now many real-time PCR kits are on the market. It is important to keep in mind that a negative PCR result does not

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rule out tuberculosis. Commercial PCR kits are not currently available for atypical Mycobacteria.

18.2.1.4 Multiplex PCR The multiplex format allows for multiple primer combinations in a single reaction instead of multiple simplex reactions. In addition, the required patient specimen size is smaller. Several studies have evaluated the use of multiplex PCR for detecting atypical organisms or Mycobacteria [29, 42, 54, 63], a combination of atypical and common organisms [78], or viral and bacterial pathogens in clinical specimens [46]. In recent years, these in-house assays have tended to be replaced by commercially available products, which are simpler to use in the diagnostic laboratory and allow easier quality assurance compared to in-house assays. Over the last 5 years, these commercial products have been offered mainly for detecting atypical organisms in clinical specimens: M. pneumoniae and C. pneumoniae [34]; M. pneumoniae, C. pneumoniae, L. pneumophila, Legionella spp, M. pneumoniae, and Bordetella pertussis [27]; C. pneumoniae, Legionella micadadei, and B. pertussis [42]; and M. pneumoniae, Coxiella burnetii, C. pneumoniae, and Legionella [12]. Multiplex PCR assays were long described as less sensitive than simplex PCR assays due to competition among primers, but two studies gave identical results with multiplex and simplex PCR tests [27, 34]. In contrast, another study showed higher sensitivity of the simplex PCR nucleic acid sequence-based amplification (NASBA) versus multiplex PCR for detecting L. pneumophila [49]. However, the lack of an appropriate reference standard for the quantitative analysis of intracellular pathogens is an obstacle to sensitivity comparisons across assays.

18.2.2 Specific PCR on Blood Samples The definitive diagnosis of pneumococcal pneumonia in noninvasive respiratory samples requires isolation of the pathogen in a blood sample. However, blood cultures are rarely positive [14]. On the other hand, pneumococcal serology has low sensitivity [8]. Therefore, PCR tests on blood were mainly described

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for S. pneumoniae [15, 55, 59]. A very recent study showed low sensitivity of PCR in plasma for detecting pneumococcal pneumonia (26–35%). However, this test may be useful for the rapid diagnosis in bacteremic patients, as sensitivity reaches 60–70% in this situation. Specificity of ply PCR was low [2]. Recently, a commercial test using multiplex PCR in serum for numerous bacterial pathogens was evaluated in neutropenic patients [82]. However, this test has not been specifically assessed in patients with lung infiltrates.

18.2.3 Universal PCR Universal PCR detects a gene found in all bacteria, usually the gene coding for 16S ribosomal RNA. The sequence of this gene allows the identification of most bacteria, without a presumptive diagnosis. This sequence includes conserved and variable regions. Universal primers are selected for conserved regions flanking a variable region, which allows differentiation of bacterial species. The amplified product is then sequenced, and the sequence is compared to all bacterial sequences contained in a database (e.g., GenBank). The sensitivity of this PCR varies across bacterial species (10–100 organisms/mL). Universal PCR has been developed chiefly for diseases such as endocarditis, meningitis, and bacteremia. It is useful in case of prior antibiotic treatment, fastidious organisms, or small inoculums. It should be used only for specimens from normally sterile sites, where it can detect only monomicrobial infections, as the presence of two or more organisms produces a mixture of non-interpretable sequences. This technique proved useful for diagnosing pleural empyema in children (40% increase in diagnostic yield compared to culture) and adults (31% increase) [47, 52]. The main organisms detected by universal PCR were S. pneumoniae, anaerobic bacteria (Fusobacterium, Prevotella), S. aureus, H. influenzae, and Streptococcus milleri group. The role for universal PCR in pulmonary samples, which are theoretically contaminated by saprophytic flora, remains to be evaluated. If cultures are negative, then universal PCR is theoretically appropriate. The likelihood of finding a mixture of bacteria by sequencing is not known. A microarray method has been found promising for the detection and identification of nine bacterial

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pathogens. For this method, universal primers amplifying a conserved region of the bacterial gyrB/parE gene are used, and the single-stranded PCR products are then characterized by hybridization on an oligonucleotide array. This technique can be used for multibacterial infections, for which PCR products cannot be directly analyzed by DNA sequencing [72].

18.3 Antigen Detection The diagnosis of pneumonia using antigen detection has made progress in recent years. Commercial antigen detection assays are now widely available for two bacterial pathogens, L. pneumophila and S. pneumoniae.

18.3.1 Legionella Urine antigen testing allows the early diagnosis and appropriate antibiotic therapy of legionellosis [41]. The capture antibody technique used in the majority of these assays is considered specific for L. pneumophila serogroup 1, which causes most legionellosis cases in humans. However, as many as 40% of cases are related to other serogroups and are missed by the assay. In a recent study on the effectiveness of urine antigen detection, pooled sensitivity was 0.74 (95% CI, 0.68–0.81) and specificity was 0.991 (95% CI, 0.984–0.997) [74]. The antigen detected is a heat-stable component of the lipopolysaccharide portion of the Legionella cell wall [44, 86]. It is generally detectable in urine as soon as 3 days after symptom onset and can persist for more than 300  days. In one study, antigen was detected in 88% of patients tested on days 1–3 after symptom onset, 80% on days 4–7, 89% on days 8–14, and 100% after day 14 [45]. The most recent method for detecting antigenuria is the immunochromatographic test (ICT) membrane assay. The ICT assay is similar to a home pregnancy test and is commercially available. The test is simple to perform and does not require special laboratory equipment, and the results are obtained within 15 min. A study found that the ICT assay for L.  pneumophila serogroup 1 was 80% sensitive and 97% specific [33]. More recently, it was suggested that

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specificity and sensitivity were higher after 30 min of incubation [17]. The use of concentrated urine samples has been suggested to increase sensitivity [7]. There is still a need for developing antigen capture assays that can diagnose infections with all Legionella species and serogroups. Twenty years ago, Tang and Toma developed a broad-spectrum ELISA that detected soluble antigens from numerous L. pneumophila serogroups and species by using rabbit antisera from a combination of intradermal, intramuscular, and intravenous inoculations over a period of 8  months [80]. Unfortunately, this test was not commercialized.

18.3.2 Streptococcus pneumoniae The recent development of a rapid ICT assay that detects the C polysaccharide cell wall antigen common to all S. pneumoniae strains has renewed interest in antigen detection. The Binax Now test uses a rabbit anti-S. pneumoniae antibody that binds to soluble pneumococcal C antigen present in the sample (NOW Streptococcus pneumoniae test; Binax, Portland, ME). The resulting complex is immobilized by a band of rabbit anti-S. pneumoniae antibodies adsorbed onto a nitrocellulose membrane sample line. A second band of goat antirabbit IgG (control line) captures excess visualizing complex. Usually, a swab is dipped into 200 mL of sample fluid and inserted into the test device. A buffer solution is added, and the device is closed. The result can be read visually after 15 min. A pink to purple color on both the sample and control lines indicates a positive result. Color on the control line only indicates a negative result and absence of color on the control line an invalid test. Pneumococcal pneumonia can be diagnosed using antigen detection in urine, BAL fluid, or pleural fluid.

18.3.2.1 Pneumococcal Antigen Detection in Urine The reported sensitivity of the ICT assay applied on urine samples ranges from 44.2% to 88.8% [18, 30, 50, 60, 71, 76]. Sensitivity is higher in bacteremic than in nonbacteremic patients and increases when urine samples are concentrated, which is usually achieved by ultracentrifugation and may last for 1–4 h [50, 60, 71].

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Several studies of the Binax Now S. pneumoniae urine antigen showed good performance for diagnosing bacteremic pneumococcal infections in adults. Sensitivity is good, ranging from 77% to 87% [10, 75, 76]. Specificities of 97–100% were found in studies that used controls with nonpneumococcal bacteremia or noninfectious disorders [75, 76]. Given its excellent specificity, this test can be considered an important tool for detecting S. pneumoniae in patients with community-acquired pneumonia of unknown etiology. It provided the diagnosis of pneumococcal pneumonia in one-fourth of cases [26]. It is important to note that the test may remain positive for several weeks after pneumococcal pneumonia [3, 50] and that patients with detectable antigen may have been colonized with S. pneumoniae. Indeed, specificity of the ICT urine test has been reported to be low in children due to nasopharyngeal carriage [31]. In adult patients, specificity was 89.7–100%, depending on the reference standard [18, 50, 71]. Antigen-positive results should be interpreted carefully in pneumonia patients with chronic bronchitis, because detectable antigen may be caused by pneumococcal carriage in the lower respiratory tract [9, 10]. In a recent study, pneumococcal urinary antigen detection (Binax Now S. pneumoniae Antigen Test) was assessed for diagnosing pneumococcal exacerbations of chronic obstructive pulmonary disease (COPD). Forty-six patients with S. pneumoniae in sputum cultures were studied during a stable period and during an exacerbation [4]. During the stable period, the antigen was detected in 10.3% of patients in nonconcentrated urine and in 41.4% of patients in concentrated urine. Corresponding proportions during exacerbations were 17.6% in nonconcentrated urine and 76.5% in concentrated urine. Specificity was evaluated by testing 72 patients whose sputum samples were negative for S. pneumoniae. ICT was positive in nonconcentrated urine from one patient and in concentrated urine from nine patients. Factors significantly associated with a positive test on concentrated urine were a history of at least one exacerbation (P = 0.024), admission for a previous exacerbation (P = 0.027), and pneumonia within the past year (P = 0.010). The only factor significantly associated with a positive test on nonconcentrated urine was pneumonia within the past year (P = 0.006). In conclusion, in COPD patients, a positive pneumococcal urinary antigen test during bronchial exacerbation or pneumonia should be

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i­nterpreted with caution, as it may reflect a prior S. pneumoniae infection [3, 4].

18.3.2.2 Pneumococcal Antigen Detection in Bronchoalveolar Lavage Fluid Little is known about the use of the ICT assay on BAL fluid samples. However, this test may be useful, as at the time of bronchoscopy most patients are receiving antibiotics, which are known to damage bacterial morphology and prevent growth in cultures. ICT could be used as an adjunct to standard cytological and microbiological studies. However, when the result is positive, the possibility of a mixed flora or superinfecting pathogen should always be considered. In a retrospective study of the Binax Now Streptococcus pneumoniae test on BAL fluid samples from patients with suspected pneumonia, 96 BAL fluid samples were tested [38]. Sensitivity was assessed using 20 samples from patients with documented pneumococcal pneumonia. Specificity was tested using BAL fluid samples from patients with nonpneumococcal disease (n = 41) and in samples containing no respiratory pathogens and a total bacterial count <104  CFU/mL (n = 35). Pneumococcal antigen was detected in 29 (30.2%) samples, with 95% sensitivity and 86.8% specificity [38]. An older study of the ICT assay found 50% sensitivity and 100% specificity [39].

18.3.2.3 Pneumococcal Antigen Detection in Pleural Fluid Pleural empyema rarely complicates communityacquired pneumonia. The rapid identification of the causal agent is required for effective treatment and a good outcome [83]. The classical microbiological technique for the diagnosis of pleural empyema is standard culture and microscopic examination. However, falsenegative results related to a small sample volume or previous antibiotic therapy are common. Testing for soluble pneumococcal antigens is a complementary approach, as the results are immediately available, and S. pneumoniae can be detected even after antibiotic initiation. In a recent retrospective study, the ICT Binax Now Streptococcus pneumoniae assay was evaluated in adults to determine whether the detection of

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pneumococcal antigen in pleural fluid was better than conventional microbiological methods for the etiologic diagnosis of pneumonia [65]. In this study, the ICT assay was performed on pleural fluid samples from 34 patients with pneumonia due to S. pneumoniae, 89 patients with effusions of nonpneumococcal origin, and 17 patients with pneumonia of unknown etiology. The ICT result was positive in 24 (70.6%) of 34 patients with pneumococcal pneumonia and negative in 83 (93.3%) of 89 patients without pneumococcal pneumonia. The pleural ICT assay was more sensitive than blood cultures (37.5%) and pleural fluid cultures (32.3%), but less sensitive than urine pneumococcal antigen detection (82.1%). However, three patients with pneumococcal pneumonia and negative ICT urine test results had a positive pleural fluid antigen test. Moreover, previous antibiotic exposure did not influence pneumococcal antigen detection in either pleural fluid or urine specimens [65]. In a retrospective study in children, S. pneumoniae was identified in 22% of samples by culture and in 69% by the Binax Now assay [64]. This test was positive in all 15 pleural fluid samples that yielded S. pneumoniae in culture, two samples that yielded Streptococcus oralis and Streptococcus salivarius in culture, and 34 culture-negative samples. Fifteen of these 34 culture-negative samples were retrospectively tested by PCR methods, and 14 were shown to contain S. pneumoniae DNA [64]. Similar high sensitivity was found in another study in children. Among 60 children with pneumococcal empyema, 17 were diagnosed only by PCR (43%) and 23 by both PCR and culture. Compared to culture and/ or PCR, the sensitivity of antigen detection was 90% [47]. More recently, the Binax Now test was evaluated on pleural fluid from 73 children admitted with pleural effusion over a period of 4 years. Sensitivity was 88% and specificity 71%, with a positive predictive value of 96% [13].

18.4 Conclusion Although these new diagnostic methods have not been specifically evaluated in patients with HM, they seem to hold considerable promise for increasing the performance of current diagnostic strategies. They should be used simultaneously on blood, BAL fluid, sputum, and

18  New Methods for Bacterial Diagnosis in Patients with Hematological Malignancies

throat swabs, and compared with conventional cultures. In the near future, molecular methods will complete, rather than replace, culture-based methods for detecting pathogens for which antibiotic resistance is a concern. Antigen detection methods may also have a role. However, a positive L. pneumophila test indicates a pulmonary infection due to serogroup 1, but a negative result does not rule out active infection due to other Legionella species. For S. pneumonia, the interpretation of the urinary antigen test results appears more difficult. A positive test may indicate simple colonization or previous pneumococcal infection, whereas the meaning of a negative test has not been evaluated in patients with HM.

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FDG-PET Imaging in Haematological Patients with Pulmonary Infiltrates

19

Tomohiko Yamane

Contents

List of Abbreviations

19.1 FDG-PET................................................................. 235

FDG PET CT MALT IVL

19.2 Lung Lesions of Haematological Malignancies............................................................ 236 19.2.1 Malignant Lymphoma............................................... 236 19.2.2 Other Haematological Malignancies........................ 237 19.3 Lung Abnormalities Associated with Haematological Disorders...................................... 237 19.3.1 Infections Associated with the Immunocompromised State...................................... 237 19.3.2 Drug-Induced Pneumonitis....................................... 238 19.3.3 Other Drug-Induced Diseases................................... 239 19.3.4 Radiation Pneumonitis.............................................. 239 19.3.5 Second Malignancies................................................ 239 19.4 Conclusion............................................................... 239 References............................................................................ 240

T. Yamane Division of Molecular Imaging, Institute of Biomedical Research and Innovation, 2-2 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan e-mail: [email protected]

2-[F-18]-Fluoro-2-deoxy-d-glucose Positron emission tomography Computed tomography Mucosa-associated lymphoid tissue Intravascular large B-cell lymphoma

19.1 FDG-PET Positron emission tomography (PET) is a diagnostic imaging technique in which the distribution of an injected radioactive tracer substance is imaged, whereby information on the functions and metabolic activity of various organs/tissues of the body is obtained. Many kinds of tracers have been developed for PET, and the most commonly used is a radioactively labelled glucose analogue, 2-[F-18]-fluoro-2deoxy-d-glucose (FDG) (Fig. 19.1). Similar to glucose, FDG is also transported into cells by the glucose transporter protein and phosphorylated to FDG-6-phosphate by the enzyme hexokinase.

Fig. 19.1  Structures of (a) glucose and (b) 2-[F-18]-fluoro-2deoxy-d-glucose

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_19, © Springer-Verlag Berlin Heidelberg 2011

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However, in contrast to glucose-6-phosphate, FDG-6phosphate does not take part in subsequent reactions of the glycolytic pathway and is retained within the cells. Malignant cells consume more glucose because of their unlimited capacity for cell division and proliferation as compared to benign cells, and these metabolic differences are exploited for differential diagnosis between these conditions by FDG-PET. Therefore in recent years, FDG-PET has become an established imaging technique for the evaluation of malignant tumours. FDG also accumulates in inflammatory tissues [1, 2]. This accumulation is considered to reflect the enhanced anaerobic glycolysis that occurs in neutrophils and macrophages infiltrating inflammatory tissues. In addition, increased vessel flow, diffusion, and the proliferative process involved in the formation of granulomas have also been suggested to underlie the FDG accumulation in inflammatory tissues [3, 4]. FDG uptake by inflammatory tissues occasionally leads to false-positive diagnosis of malignant tumours. However, FDG-PET can also be a very useful tool for the diagnosis, evaluation, and follow-up of some inflammatory conditions.

19.2 Lung Lesions of Haematological Malignancies FDG-PET is an effective tool for the diagnosis of various malignant diseases; among these, it has been reported to be particularly useful for the diagnosis of haematological malignancies, such as malignant lymphoma. Pulmonary infiltrates associated with haematological malignancies can also usually be visualized by FDG-PET, and the technique has been used for the evaluation of these malignancies, the distribution of the lesions, and also the effects of therapy. When pulmonary abnormalities are suspected in patients with haematological disorders; however, FDG-PET is not usually included in the routine initial examination. The examinations that are usually performed are plain radiography and computed tomography [5] as radiological investigations, followed by bronchoalveolar lavage [6], biopsy [7], and/or biochemical examinations [8].

T. Yamane

Thus, FDG-PET is not usually the most commonly employed method for the diagnosis of lung lesions associated with haematological malignancies. However, it is important to understand how lung lesions are visualized on FDG-PET, because they sometimes occur as a component of the systemic disease. In addition, FDG-PET may be effective for selecting the most appropriate biopsy area [9]. FDGPET findings of lung lesions associated with some haematological diseases are described in the following sections.

19.2.1 Malignant Lymphoma In relation to haematological disorders, numerous reports have demonstrated the efficacy of FDG-PET for the diagnosis, in particular, of malignant lymphoma [10,11]. Pulmonary lesions of lymphoma, as a component of systemic lymphoma, can also be visualized on FDG-PET. In addition, characteristic lung findings associated with mucosa-associated lymphoid tissue (MALT) lymphoma and intravascular lymphoma have been investigated.

19.2.1.1 MALT Lymphoma FDG uptake by MALT lymphomas is generally known to be lower as compared with that by other high-grade lymphomas [12–15]. However, some reports have suggested a high sensitivity of FDG-PET for the diagnosis of pulmonary MALT lymphomas [16–18]. MALT lymphomas are most commonly detected in the stomach, where physiological FDG uptake is also frequently observed [19]. Background uptake and tumour morphology have been suggested as some of the factors that might influence the degree of uptake by these gastric tumours; however, the precise nature of their influence is unclear. Pulmonary MALT lymphomas are usually characterized by heterogeneous patterns on FDG-PET, akin to the CT findings, although some cases show a homogenous uptake pattern [18, 20–22]. Further investigations are needed to clarify the mechanisms of FDG uptake and clinical significance of the FDG-PET findings in patients with pulmonary MALT lymphoma.

19  FDG-PET Imaging in Haematological Patients with Pulmonary Infiltrates

19.2.1.2 Intravascular Lymphoma Intravascular large B-cell lymphoma (IVL), classified as a subtype of diffuse large B-cell lymphoma by the World Health Organization [23], is rare and characterized by clonal proliferation of neoplastic lymphoid cells within the capillary lumina of small blood vessels. The major organs involved in IVL are mainly the bone marrow, spleen, liver, central nervous system, skin, and lymph nodes [24, 25]. Pulmonary IVL is uncommon and rather difficult to diagnose. Although some articles have described the CT findings of IVL as being characterized by diffuse or patchy interstitial infiltrates [26–28], there have also been cases where final histopathological confirmation of the diagnosis was obtained only at autopsy [29, 30]. A case of IVL is reported in the last part of this book by Dr. Darmon and coworkers. In a case report of pulmonary IVL without any abnormal findings on CT or gallium-67 scintigraphy, only FDG-PET revealed diffuse pulmonary uptake [31]. Physicians tend to hesitate to undertake invasive approaches, such as biopsy, for the diagnosis when CT reveals no abnormalities. Therefore, FDG-PET may play an important role in the diagnosis of pulmonary IVL. Articles dealing with the FDG-PET findings of pulmonary IVL are limited, and the sensitivity and specificity of the technique for the diagnosis of this condition or the characteristic findings of IVL on FDG-PET are unknown. Therefore, further research may provide greater insight regarding the clinical significance of FDG-PET findings in cases with IVL.

19.2.2 Other Haematological Malignancies There are some reports of the FDG-PET findings in multiple myeloma and plastocytoma [32] and leukaemia [33–35]. However, the effectiveness of FDG-PET for the diagnosis of these diseases has not been fully investigated. Although the use of other tracers that can reflect the cell proliferative activity, such as [F-18]fluorothymidine, has been discussed for evaluating the therapeutic effect in cases of leukaemia [36], further investigations are necessary. While lung lesions are well known to occur in leukaemia [37–39], the FDGPET findings have not yet been well characterised. The

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lung lesions of leukaemia may be expected to be ­FDG-avid, and the clinical significance of FDG-PET in this disease must be discussed.

19.3 Lung Abnormalities Associated with Haematological Disorders In patients with haematological disorders, various pulmonary abnormalities such as opportunistic infections or drug-induced disorders may be encountered during the clinical course [6]. These lung disorders can be life threatening, and therefore, immediate diagnosis is essential. The entire body is usually imaged in FDG-PET, and the imaging is often repeated to evaluate the effect of therapy or for patient follow-up after initial treatment of a malignant tumour. Occasionally, lung abnormalities are unexpectedly detected even in patients without lesions in the lung at the initial examination. Moreover, an integrated PET and CT system has recently been introduced for PET/CT, whereby morphological information can be evaluated simultaneously with functional imaging. Some diseases that may be diagnosed by FDG-PET during the treatment of haematological disorders are mentioned in the following section.

19.3.1 Infections Associated with the Immunocompromised State Patients with haematological disorders, especially those in the immunocompromised state during chemotherapy, are at an increased risk of developing various types of infectious diseases. As FDG accumulates in inflammatory tissues, the findings may mimic those of malignant tumours. For example, pneumocystis pneumonia [40, 41], tuberculosis [42], cryptococcus infection [43, 44], and aspergillus infection [45] have been reported as FDGavid lung lesions that need to be differentiated from lung malignancy. Diverse uptake patterns can be visualised on FDG-PET, such as diffuse, nodular, and patchy, and it is difficult to diagnose the causative pathogen or differentiate between malignant and inflammatory lesions based on the uptake pattern visualised on FDG-PET

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alone. Under such circumstances, additional delayed images acquired at 120–160 min post injection of FDG may increase the diagnostic usefulness of FDG-PET [46]. FDG-PET combined with other diagnostic modalities, such as CT, and relevant microbiological and laboratory tests are useful.

19.3.2 Drug-Induced Pneumonitis Various drug-induced disorders of the lung may ­be induced during chemotherapy of haematological ­disorders. Drug-induced pneumonitis caused by

a

Fig. 19.2  (a) Initial FDG-PET image of a diffuse large B-cell lymphoma. Abnormal uptake is observed corresponding to the bulky mass in the left abdomen and in the left axillary, paraaortic, and para-external iliac artery lymph nodes (arrows). No increased uptake was observed in the lung. (b) FDG-PET after five courses of chemotherapy. Decreased, but persistent uptake by the bulky mass in the left abdomen was observed (arrow), whereas the uptake by the other lymph nodes was no longer

chemotherapeutic agents is not uncommon and may occasionally be fatal. Such pneumonitis may be detected as diffuse uptake on FDG-PET, corresponding to the opacity visualised on CT [47–50]. In one case report of diffuse lung uptake of FDG suspected to be caused by drug-induced pneumonitis during chemotherapy for malignant lymphoma [51], chest CT obtained on the same day did not reveal any abnormalities (Fig.  19.2); ­however, patchy ground-grass opacities on the CT appeared 3  days later; therefore, it appears that FDG-PET may be more sensitive than conventional CT for the early lung changes associated with drug-induced pneumonitis. Therefore, patients with haematological disorders showing diffuse lung

b

seen. Although diffuse lung uptake was observed (arrowheads), patient did not complain of dyspnea. (c) Computed tomography performed after five courses of chemotherapy, immediately after FDG-PET. No abnormal findings are apparent. (d) Computed tomography performed 3 days after the initial FDG-PET and CT performed after five courses of chemotherapy. Patchy groundgrass opacities are seen throughout the lung fields (Modified and reprinted with permission of [51])

19  FDG-PET Imaging in Haematological Patients with Pulmonary Infiltrates

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c

d

Fig. 19.2  (continued)

uptake on FDG-PET during chemotherapy should be examined carefully, even if the CT reveals no abnormalities.

19.3.3 Other Drug-Induced Diseases Other complications that might develop during the treatment of haematological disorders are also known, such as sarcoidosis occurring in association with interferon therapy [52] or alveolar proteinosis [53]. Although there are no studies directly comparing the FDG-PET findings in these diseases, they can nevertheless be detected by FDG-PET [54, 55]. FDG-PET may be useful for the diagnosis of these diseases.

19.3.4 Radiation Pneumonitis One of the major complications of radiation therapy is pneumonitis. FDG is known to accumulate in lesions of radiation pneumonitis, corresponding to the consolidation on CT, and the degree of uptake has been reported to be related to the radiation dose and the clinical symptom severity [56, 57].

19.3.5 Second Malignancies Occurrence of second malignancy is known in patients treated for malignant lymphoma, and lung cancer is one of the most frequently encountered second

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systemic lymphoma. Characteristic lung findings may be observed in cases of MALT lymphoma and IVL, and FDG-PET may be useful for the diagnosis of these conditions. In addition, some complications that might occur during the treatment of haematological disorders, such as infectious diseases or druginduced pneumonitis, may also be detected by FDG-PET. It is possible that subtle changes associated with these conditions may be detected earlier by FDG-PET than by CT; therefore, careful examination of such patients is necessary even if no abnormalities are detected on CT.

References

Fig. 19.3  Initial FDG-PET image of a mantle cell lymphoma. Abnormal uptake is observed in the bulky mass in the left abdomen and in the axillary, hilar, and inguinal lymph nodes bilaterally. Higher uptake was observed in left hilar area (arrow), which was finally diagnosed as adenocarcinoma of the lung

malignancies [58, 59]. Second malignancies may be difficult to distinguish from the primary haematological disorder on FDG-PET (Fig. 19.3). Differences in the intensity of uptake may be significant for distinguishing between them, but it is important to take into consideration the clinical data and the results of other imaging studies to make a precise diagnosis.

19.4 Conclusion FDG-PET is an effective tool for the diagnosis of haematological malignancies as well as other malignant tumours. Pulmonary lesions of lymphoma can be visualised on FDG-PET, as a component of

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T. Yamane 52. Doyle MK, Berggren R, Magnus JH (2006) Interferoninduced sarcoidosis. J Clin Rheumatol 12:241–248 53. Chung JH, Pipavath SJ, Myerson DH et al (2009) Secondary pulmonary alveolar proteinosis: a confusing and potentially serious complication of hematologic malignancy. J Thorac Imaging 24:115–118 54. Braun JJ, Kessler R, Constantinesco A et al (2008) 18F-FDG PET/CT in sarcoidosis management: review and report of 20 cases. Eur J Nucl Med Mol Imaging 35:1537–1543 55. Hsu CW, Liu FY, Wang CW et al (2009) F-18 FDG PET/CT in pulmonary alveolar proteinosis. Clin Nucl Med 34: 103–104 56. Hart JP, McCurdy MR, Ezhil M et al (2008) Radiation pneumonitis: correlation of toxicity with pulmonary metabolic radiation response. Int J Radiat Oncol Biol Phys 71:967–971 57. Guerrero T, Johnson V, Hart J et al (2007) Radiation pneumonitis: local dose versus [18F]-fluorodeoxyglucose uptake response in irradiated lung. Int J Radiat Oncol Biol Phys 68:1030–1035 58. Andre M, Mounier N, Leleu X et al (2004) Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma with the ACVBP regimen: a GELA cohort study on 2837 patients. Blood 103:1222–1228 59. Sacchi S, Marcheselli L, Bari A et al (2008) Second malignancies after treatment of diffuse large B-cell non-Hodgkin’s lymphoma: a GISL cohort study. Haematologica 93: 1335–1342

What Has Been Learned from Postmortem Studies?

20

Stephen M. Pastores, Alina O. Dulu, and Shilpa A. DeSouza

Contents 20.1 Introduction............................................................. 243 20.2 Infectious Findings................................................. 244 20.2.1 Invasive Fungal Infections........................................ 244 20.2.2 Pneumocystis Jiroveci (Formerly Carinii) Pneumonia................................................................ 245 20.2.3 Bacterial Infections................................................... 245 20.2.4 Viruses...................................................................... 245 20.2.5 Toxoplasmosis.......................................................... 246 20.3 Noninfectious Pulmonary Findings....................... 246 20.3.1 Diffuse Alveolar Damage......................................... 246 20.3.2 Diffuse Alveolar Hemorrhage.................................. 246 20.3.3 Lymphomatous or Leukemic Infiltration.................. 247 20.3.4 Pulmonary Thromboembolism................................. 247 20.3.5 Bronchiolitis Obliterans with Organizing Pneumonia and Bronchiolitis Obliterans.................. 248 20.3.6 Pulmonary Veno-occlusive Disease.......................... 248 20.3.7 Pulmonary Alveolar Proteinosis............................... 249 20.4 Discrepancies Between Clinical and Postmortem Autopsy Findings............................... 249 20.5 Summary................................................................. 251 References............................................................................ 251

S.M. Pastores (*) and S.A. DeSouza Department of Anesthesiology and Critical Care Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, 1275 York Avenue C-1179, New York, NY 10065, USA e-mail: [email protected] A.O. Dulu Division of Critical Care Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA

20.1 Introduction Infectious and noninfectious pulmonary complications occur in 30–60% of patients with hematological mali­ gnancy and recipients of hematopoietic stem cell tran­ splantation (HSCT) and are associated with signifi­cant morbidity and mortality [1]. In allogeneic HSCT pati­ ents who develop respiratory failure requiring mechanical ventilation, the intensive care unit (ICU) and hospital mortality rates often exceed 80% and 85%, respectively [2–5]. The factors that contribute to the development of pulmonary complications in these patients include immunologic defects due to the underlying disease and its treatment, conditioning regimens, development of graft-versus-host disease (GVHD), and the type of HSCT [2, 6, 7]. The spectrum of pulmonary complications in patients with hematological malignancy and HSCT recipients is changing because of recent advances in antineoplastic therapies, such as the use of monoclonal antibodies and other targeted agents, increased application of HSCT for older patients, widespread use of prophylactic antibiotics and novel antimicrobial agents, and advances in supportive care [8]. Prompt investigation and diagnosis of pulmonary complications in patients with hematological malignancies are essential to improving patient survival. Unfortunately, despite the technological advances in diagnostic testing and imaging modalities, obtaining an accurate clinical diagnosis in these patients remains difficult and at times is made only at the time of the postmortem autopsy examination. Autopsy rates in cancer patients are much lower (13–34%) as compared to general medical and surgical patients (53–64%) [7– 9]. This probably reflects the unwillingness on the The authors state that they do not have any conflicts of interest.

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_20, © Springer-Verlag Berlin Heidelberg 2011

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Table 20.1  Pulmonary findings on postmortem studies in patients with hematologic malignancy including HSCT recipients Infectious Non-infectious Fungal Invasive pulmonary aspergillosis Candida bronchopneumonia Zygomycetes Trichosporon spp. Fusarium spp. Chaetomium spp. Pneumocystis jiroveci pneumonia

 iffuse alveolar damage D Diffuse alveolar hemorrhage Lymphoma/leukemia Pulmonary thromboembolism Bronchiolitis obliterans organizing pneumonia Bronchiolitis obliterans Pulmonary veno-occlusive disease Pulmonary alveolar proteinosis

Bacterial Vancomycin-resistant enterococci Legionella spp. Stenotrophomonas maltophilia Staphylococcus epidermidis Staphylococcus aureus Streptococcus pneumoniae Pseudomonas aeruginosa Serratia spp. Other gram-negative bacilli and streptococcus spp. Viral Cytomegalovirus Herpes simplex virus Respiratory syncytial virus Measles virus Parasitic Toxoplasmosis

part of physicians and family members to subject the cancer patient to the same level of scrutiny applied to other major illnesses in determining the primary and contributory causes of death [9]. Additional concerns include legal issues regarding exposition of physicians’ errors and non-reimbursement for postmortem examinations [10]. This chapter will review the infectious and noninfectious pulmonary findings that have been described at autopsy in patients with hematological malignancies, including blood and bone marrow transplant recipients. In addition, we discuss the frequently noted

diagnostic discrepancies between premortem clinical diagnoses and postmortem autopsy findings in these patients. Finally, we highlight the difficulties in diagnosing many of these conditions antemortem and emphasize the important role of the postmortem examination in accurately establishing the cause of death. Table  20.1 lists the infectious and non-infectious ­pulmonary disorders reported in autopsy studies of patients with hematologic malignancy, ­including HSCT recipients.

20.2 Infectious Findings 20.2.1 Invasive Fungal Infections The incidence of invasive fungal infections in patients with hematologic malignancies has increased steadily over the past three decades [11]. This has been attributed to improvements in the prevention or preemptive treatment of bacterial infections and other opportunistic pathogens, particularly Candida and cytomegalovirus; increased administration of chemotherapies with profound and prolonged immunosuppressive effects on T-cell function (e.g., purine nucleoside analogs, antiT-cell immunoglobulin, and monoclonal antibodies); and the growing number of allogeneic and nonmyeloablative transplantation procedures that carry a higher risk for chronic GVHD [12]. Patients with hematologic malignancies, especially in the neutropenic state after aggressive chemotherapy or HSCT and HSCT recipients with GVHD, are particularly susceptible to invasive fungal infections [13]. Approximately 20–50% of patients with hematological malignancies and HSCT recipients have evidence of invasive fungal infections at autopsy [8]. These include invasive aspergillosis and fungal infections due to Candida spp., Zygomycetes spp., Trichosporon spp., Fusarium spp., and various Chaetomium species. In neutropenic patients with acute leukemia, the histopathological pattern of invasive pulmonary aspergillosis (IPA) is characterized by scant inflammation, hyphal angioinvasion with a high fungal burden, and extensive coagulative necrosis [12, 14]. In contrast, among HSCT recipients with GVHD, the histopathological findings consist of severe lung inflammation and less abundant Aspergillus burden. Several autopsy

20  What Has Been Learned from Postmortem Studies?

studies in HSCT recipients have shown that IPA is frequently not diagnosed antemortem or persistent despite diagnosis by sputum or bronchoalveolar lavage (BAL) cultures or by serum galactomannan assay and treatment with amphotericin B [8, 15–21]. In recent years, treatment of IPA with voriconazole has led to better responses, improved survival rates, and fewer side effects than amphotericin B [22]. Autopsy studies have assisted in describing and confirming the immune reconstitution inflammatory syndrome (IRIS) in patients with IPA who are recovering from the neutropenia [23]. When clinical and radiologic worsening coincides with neutrophil recovery, it is usually assumed that this deterioration is related to prog­ ressive aspergillosis, prompting changes in patient man­agement. However, its temporal relation with neutrophil recovery suggests that it may be caused by IRIS. The patients who died during the first month had no evidence of aspergillosis at autopsy. Finally, autopsy studies have proved helpful in documenting the efficacy of systemic antifungal therapy and surgery for IPA [24]. Since the early 1990s, the incidence of invasive candidiasis (candidemia and/or hepatosplenic candidiasis) has continued to decrease due to effective antifungal prophylaxis and empirical treatment of high-risk patients with echinocandins and voriconazole [11]. Mucosal damage is a risk factor for invasive candidiasis among patients receiving antineoplastic therapy. HSCT recipients who received conditioning regimens with total body irradiation and patients treated with chemotherapy regimens containing high-dose cytarabine or an anthracycline have an increased risk of developing invasive disease. In recent years, there has been an increase in bloodstream infections caused by  non-albicans Candida species such as Candida glabrata and C. krusei. The diagnosis of invasive candidiasis is difficult to prove due to the lack of specific clinical features and the low sensitivity of blood cultures to isolate Candida, especially in patients receiving fluconazole prophylaxis [25]. Difficult-to-treat opportunistic molds, such as Zygomycetes, Trichosporon spp., and various Chae­ tomium spp., including C. atrobrunneum, C. strumar­ ium, C. globosum, C. perlucidum, and C. cinereus are being described with increasing frequency on autopsy studies in patients with hematologic malignancies [12, 26–31]. Pulmonary involvement with these mold infections is characterized by tissue necrosis from angioinvasion and subsequent thrombosis. As with many

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fungal infections, diagnosis of these infections is often not possible until autopsy. Treatment modalities ­usually involve lipid-based amphotericin B formulations and surgical debulking or debridement in selected cases [32].

20.2.2 Pneumocystis Jiroveci (Formerly Carinii) Pneumonia Pneumocystis jiroveci pneumonia (PCP) remains a serious infection in patients with acute and chronic leukemias, myelodysplastic syndrome, and HSCT recipients [8]. However, diagnosis of PCP is frequently obtained by bronchoalveolar lavage with or without lung biopsy; thus, the diagnosis is made on autopsy in only a minority of cases.

20.2.3 Bacterial Infections Bacterial pneumonias caused by Pseudomonas aerugi­ nosa, Streptococcus spp., Staphylococcus aureus, Serratia spp., and Legionella pneumophila have been described on autopsy studies in patients with hematologic malignancy and HSCT recipients [33]. As the majority of these patients commonly receive empiric antimicrobial therapy during the initial diagnostic workup for infection, very few autopsy studies report unusual bacterial infections. A single center autopsy series of 15 patients with hematological malignancies found multidrug-resistant strains such as Enterococcus faecium to be very prevalent [34]. Two coagulase-­ negative Staphylococcus epidermidis strains were also noted. A few autopsy case reports have also described lethal pulmonary hemorrhage due to Stenotrophomonas maltophilia [35].

20.2.4 Viruses The incidence of autopsy-proven cytomegalovirus (CMV) pneumonia in patients with hematologic malignancy and HSCT recipients has been decreasing in recent years as a result of improvements in early diagnosis and treatment and more effective preventive strategies [36]. However, it is also possible that the

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declining rate of autopsies may account for the decrease in the number of reported CMV pneumonias. Other etiologies of viral pneumonias that have been described in autopsy reports include infection due to herpes simplex virus, respiratory syncytial virus (RSV) [37], and measles virus [38].

20.2.5 Toxoplasmosis Reactivation of latent Toxoplasmosis is a rare but wellrecognized opportunistic infection in immunocompromised patients. Besides encephalitis, the other common presentation with Toxoplasma gondii infection is interstitial pneumonitis. Because of its non-specific clinical and radiological presentation and its lethal outcome, toxoplasmosis is often misdiagnosed and only revealed at autopsy [39]. Toxoplasmic pneumonitis follows the same pathogenetic mechanism, but occurs less frequently than either toxoplasmic encephalitis or other opportunistic pneumonias, such as PCP. Diagnosis is based upon a high degree of clinical suspicion and demonstration of T. gondii in BAL fluid and/or lung biopsy specimens. Widely disseminated necrotic areas with numerous cysts of Toxoplasma gondii are commonly reported in autopsy cases.

20.3 Noninfectious Pulmonary Findings Noninfectious pulmonary complications account for up to 70% of autopsy findings in patients with hematologic malignancies, particularly in HSCT recipients. The most common complications are diffuse alveolar damage (DAD) and diffuse alveolar hemorrhage (DAH) [8].

20.3.1 Diffuse Alveolar Damage Diffuse alveolar damage (DAD) is a nonspecific finding at autopsy often in association with various infectious and noninfectious etiologies, such as shock, aspiration, alveolar hemorrhage, peri-engraftment respiratory distress syndrome, drug toxicity, and radiation therapy. It is characterized by the presence of alveolar injury and the absence of active lower respiratory tract infection.

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DAD has been reported at autopsy in 63.5% of patients with treated leukemia and lymphoma and close to 50% among HSCT patients [7, 8]. Infections as the cause of DAD are identified on autopsy in only a third of HSCT patients, while approximately 20% have DAH. In over 50% of patients with DAD, no etiology is determined, and these patients are considered as having idiopathic pneumonia syndrome (IPS). It is possible that empirically treated previous infections could have caused the histological changes noted in patients classified as having IPS. Only one third of the cases of DAD are diagnosed antemortem [8]. Given that almost half of the cases of DAD may be secondary to IPS, the role of ­corticosteroids may need to be furthered studied.

20.3.2 Diffuse Alveolar Hemorrhage Diffuse alveolar hemorrhage (DAH) is a clinical syndrome characterized by the acute onset of alveolar infiltrates, bloody bronchoalveolar lavage, and hypoxemia in the absence of infection [1, 40]. The incidence of DAH ranges from 1–5% to 3–7% in autologous and allogeneic HSCT recipients, respectively [41–43]. A few case reports have been described in patients with acute leukemia more commonly in association with chemotherapy [44–46]. DAH has also been described in patients undergoing an umbilical cord HSCT [47, 48]. The majority of patients with DAH develop severe respiratory failure with high mortality rates. Vascular damage and inflammation from chemotherapy and radiation therapy used in the con­ditioning regimen and immune-mediated events including GVHD have been implicated in the pathogenesis of DAH [41, 43, 49]. Wojno et al. reported that 41% of 37 allogeneic HSCT patients who underwent autopsies had extensive pulmonary hemorrhage, which was thought to have led to severe respiratory failure and death [49]. These patients were subdivided into those with significant acute GVHD and those without. Of the patients with acute GVHD, 59% died of acute respiratory failure secondary to DAH compared with 25% of those without GVHD. Pulmonary hemorrhage was also independently found to be associated with pre-transplant total body irradiation. Although pulmonary and systemic infections cause alveolar damage through similar mechanisms [50]. infection-associated alveolar damage has traditionally been excluded from analyses of DAH. Autopsy studies have shown

20  What Has Been Learned from Postmortem Studies?

that pulmonary infections are frequently underdiagnosed in HSCT recipients; thus, patients with alveolar hemorrhage and underlying undetected infections can be misclassified as having DAH [7, 8, 51]. Because inflammation is thought to play a role in the pathogenesis of post HSCT-DAH, high-dose steroids have been used for its treatment, based on anecdotal case reports and small retrospective series [52, 53]. Other treatment modalities that have been used for DAH in HSCT recipients include epsilon aminocaproic acid and recombinant factor VIIa [54, 55]. Unfortunately, the mortality from DAH in HSCT recipients remains high because of misdiagnosis and lack of effective treatments.

20.3.3 Lymphomatous or Leukemic Infiltration Primary pulmonary lymphomas are very uncommon, especially those arising from bronchus-associated lymphoid tissue (BALT) and have a low mortality. They represent 4% of the extranodal non-Hodgkin’s lymphomas (NHLs) and only 0.5% of all primary pulmonary malignant neoplasms and less than 1% of lymphomas. Eighty percent of the cases are low-grade B-cell lymphomas, which are slow growing and respond well to therapy. Autopsy case reports suggest that pulmonary BALT lymphoma can remain restrictive to the thorax for long periods before dissemination, but tend to relapse frequently. Lymphomatous involvement of the lung is common and occurs in 24% and 38%, respectively, of patients with Hodgkin’s lymphomas (HL) and NHL [56]. Typical findings in the lung include peribronchialperivascular, nodular, alveolar, interstitial, and pleural involvement. Peripheral T-cell lymphomas also involve the lung frequently, 20% at diagnosis and a further 20% during the course of the disease. The nodular pattern is a characteristic of lung infiltration in HL, but no differences could be detected in the subtypes. Pulmonary parenchymal involvement by multiple myeloma cells is very rare and described on autopsy in few case reports. The antemortem diagnosis of lung involvement by myeloma is difficult to make as infections and alveolar hemorrhage can have the same radiologic features.

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Leukemic infiltration of the lungs may occur in 20–30% of hyperleucocytic patients with acute myeloid leukemia (AML). Pulmonary infiltrates are usually microscopic and invariably associated with hyperleukocytosis. There are autopsy case reports of pulmonary leukemia as a cause of pulmonary infiltrates, even in non-hyperleukocytosis AML patients with low blast counts. Radiographically, patients present with an airspace disease with a ­diffuse interstitial reticular pattern in cases of hyperleukocytosis similar to cases of infectious pneumonia. Pulmonary leukostasis syndrome involves the occlusion of small blood vessels in the lungs and typically occurs with a WBC count of greater than 100,000 per mL. The increased number of WBCs causes blood viscosity to rise due to the decreased deformability of the abnormal leukocytes, resulting in cell clumping and stasis in the microvasculature, leading to severe hypoxemic respiratory failure. Autopsy studies reveal extensive infiltration by leukemic cells in the pulmonary vasculature; pulmonary infarction with hemorrhage is also noted. [57] Rarely, lung involvement by intravascular large B-cell lymphoma (IVLBCL) is noted on autopsy [58]. Early diagnosis is difficult as neither computed tomography nor 67-gallium scintigraphy can detect lung involvement. However, 18-fluro-deoxyglucose positron tomography (FDG-PET) may be a powerful tool for the early diagnosis of IVLBCL with pulmonary involvement [59].

20.3.4 Pulmonary Thromboembolism Autopsy studies show that pulmonary thromboembolism (PTE) infrequently complicates the course of patients with acute leukemia and severe thrombocytopenia, and HSCT recipients with an incidence rate ranging from 1% to 6.3% [8]. [60] Patients with acute leukemias commonly have clinically silent haemostatic abnormalities, but some may show clinical manifestations, including venous thromboembolism, pulmonary embolism, ­disseminated intravascular coagulation, and life-threatening thrombohemorrhagic syndrome. The pathogenesis of PTE is complex and multifactorial and may involve tumor cell-derived procoagulant, fibrinolytic or proteolytic factors, and inflammatory cytokines, which affect clotting activation. Chemotherapy and anti-angiogenic drugs also increase the thrombotic risk in patients with

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lymphoma, acute leukemia, and multiple myeloma. Infectious complications are another important factor: endotoxins from gram-negative bacteria induce the release of tissue factor (TF), tumor necrosis factor (TNF), and interleukin-1 (IL-1), and gram-positive organisms can release bacterial mucopolysaccharides that directly activate factor XII. Needleman et al. reviewed 80 consecutive autopsies in leukemia patients and found three patients with previously undiagnosed PTE, all of whom had been severely thrombocytopenic. However, Candida forms were abundant in the thromboemboli in all three patients, with some containing septate hyphal forms consistent with Mucor or aspergillosis. No vessel wall invasion or necrosis was noted, and fungus was not shown to be present in pulmonary vessels in segments of the lung not involved with thromboembolism [60]. Leukemic patients may also be affected by other prothrombotic factors, including hyperleukocytosis, increased TF expression and activation, and the prothrombotic properties of therapeutic agents, such as all-trans retinoic acid and L-asparaginase, which can induce thrombosis involving multiple organs. A higher index of suspicion may lead to the diagnosis, but the signs and symptoms of PTE in patients with hematologic malignancy are variable and nonspecific as with PTE in other populations.

20.3.5 Bronchiolitis Obliterans with Organizing Pneumonia and Bronchiolitis Obliterans The majority of patients with hematological malignancies who develop organizing pneumonia (BOOP) have been exposed to various chemotherapeutic agents, including cytarabine and anthracyclines as well as radiation therapy. [61, 62] In one autopsy series, Sharma et al. reported on 71 patients who had undergone HSCT, of whom 3% had BO and 1% had BOOP [8]. Unusual histological variants have also been described, including a case report of acute fibrinous and organizing pneumonia following HSCT in a patient with AML [63] characterized by prominent intraalveolar fibrin deposition and organizing pneumonia. The radiographic presentation revealed patchy consolidation in the lower lobes and a diffuse miliary pattern. Clinically, these cases can have subacute presentations similar to cryptogenic organizing pneumonia or have

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more rapid progression with clinical features similar to ARDS. BOOP and BO are rare autopsy findings, which may be because infections are being treated aggressively, and often patients not responding to antibiotics and with no clinical evidence of infections are given a trial of corticosteroids. Yokoi et  al. reported bronchiolitis obliterans (BO) on autopsy in 8 of 81 patients who underwent allogeneic BMT with AML or ALL. All patients received conditioning regimens with total body irradiation and cyclophosphamide with or without busulfan or cytosine arabinoside. Immunosuppressive therapies were administered to all patients after BMT, including methotrexate with or without cyclosporine. The onset of respiratory symptoms was 110–430  days after BMT, and the symptoms were non-productive cough, dyspnea, fever, chest pain, and pneumothorax. Seven patients died of progressive respiratory failure and one of relapsed leukemia. Coexistent infections included CMV, varicella zoster, Mycobacterium tuberculosis, and Aspergillus [21]. Paz et  al. also described two patients who underwent autologous BMT for lymphoma and developed rapidly progressive respiratory insufficiency on post-transplant day 90 and 273. Despite aggressive immunosuppressive therapy, both patients died of respiratory failure. Autopsy studies revealed histological evidence of bronchiolitis obliterans [64].

20.3.6 Pulmonary Veno-occlusive Disease Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension that is characterized histopathologically by intimal proliferation and fibrosis of the pulmonary venules and small veins leading to progressive vascular obstruction [65]. The etiology of PVOD remains unclear. It has been reported as an unusual complication of both myeloablative allogeneic, autologous and cord HSCT, suggesting that it might be regimen-related toxicity [65–70]. Surgical lung biopsy provides definitive diagnosis [71]. PVOD carries a poor prognosis, with most reported patients experiencing progressive disease and death within 2 years of diagnosis [72]. Autopsy findings reveal intimal fibrosis of most of the pulmonary veins, with no significant intraluminal thrombi or arterial changes [69]. Treatment

20  What Has Been Learned from Postmortem Studies?

recommendations are anecdotal. Steroids and heparin have been reported to possibly improve outcomes [66].

20.3.7 Pulmonary Alveolar Proteinosis Autopsy studies in patients with hematologic malignancy (particularly with myelodysplastic syndrome) and following HSCT have revealed rare cases of secondary pulmonary alveolar proteinosis (PAP) characterized by intra-alveolar accumulation of surfactant components and cellular debris, with minimal interstitial inflammation or fibrosis [73–75]. Secondary PAP is frequently noted among patients with hematologic malignancies who develop fungal infection, especially pulmonary aspergillosis. KL-6 protein is produced by type II alveolar pneumocytes and can be helpful in establishing an early diagnosis of PAP [74, 76]. The standard therapy for PAP with hematological malignancy has not yet been firmly established. The administration of GM-CSF has been suggested to activate the alveolar macrophages and increase the rate of surfactant clearance [73]. Case reports indicate that the prognosis of PAP with leukemia is very poor because of the high frequency of superinfections in the affected alveoli [73, 75].

20.4 Discrepancies Between Clinical and Postmortem Autopsy Findings Several autopsy series have reported diagnostic discrepancies between premortem clinical diagnosis and postmortem autopsy findings ranging from 5% to 64% in patients with hematologic malignancy and HSCT recipients (Table 20.2) [15, 77–83]. The Goldman criteria are commonly used to categorize discrepancies between clinical and pathological diagnoses or causes of death [84]. Class 1 discrepancies are defined as missed major diagnoses with potential adverse impact on survival and would have changed management. Class II discrepancies are missed major diagnoses with no potential impact on survival and that would have not changed therapy. Class III discrepancies are defined as missed minor diagnoses related to terminal disease, but not related to the cause of death, and Class IV are other missed minor diagnoses.

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Gerain et  al. reported a 59% major discrepancy rate in 34 cancer patients who were admitted to a medical oncological ICU over an 11-month period. [77] The majority of major discrepancies were due to complications of the cancer itself or its treatment (such as non-cardiogenic pulmonary edema, acute hemorrhage, and pulmonary embolism) rather than infection. Pastores et  al. reported a major missed diagnosis rate of 26% in 86 autopsies performed on cancer patients who died in a medical-surgical ICU [78]. Of the 86 patients, 25 (40%) had undergone HSCT, 18 (29%) had either leukemias or lymphomas, 19 (31%) had solid tumors, and 24 (28%) were surgical cancer patients. Among the patients with discrepancies 54% had class I discrepancies, 32% had class II discrepancies, and 14% had both class I and class II discrepancies. Of the 22 discordant cases, 6 had hematological malignancies and 4 underwent HSCT. Opportunistic infections due to viral, fungal, bacterial, and parasitic organisms and cardiac complications were the most common class I discrepancies. The majority of Class II discrepancies were accounted for by cardiopulmonary complications due to pulmonary embolism and thrombotic endocarditis. The study was limited by the retrospective study design and selection bias that may have occurred as physicians and family members of patients with premortem diagnostic uncertainty would have been more likely to pursue an autopsy. Xavier et al. reported a class I discrepancy rate of 31.3% in 118 autopsies of patients with hematological malignancies or severe aplastic anemia [79]. The most common diagnoses causing these discrepancies were hematological disease, pneumonia, and gastrointestinal hemorrhage. Class I discrepancies were more common in elderly patients (>64  years) and in patients who had not received ­previous specific treatment for the hematological malignancy, had not been treated with bone marrow or peripheral blood HSCT, or had not been treated in a specialized hematology unit. Seftel et al. reported a discrepancy rate of 64% (34% major, 30% minor) in 48 autopsies of patients who underwent HSCT (blood and bone marrow) [82]. Infectious complications, including pulmonary aspe­rgillosis, candidiasis, and infective endocarditis, accounted for the majority of the major discrepancies. Hoffmeister et al. found a 26% discrepancy rate (4% major, 23% minor) in 111 autopsies of patients who had undergone HSCT [83]. In contrast, Al Saidi et al. found a

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Table  20.2  List of selected studies describing discrepancies between premortem and postmortem autopsy diagnoses in patients with hematologic malignancy including HSCT recipients

Seftel et al. (2007) n = 48 Class I (n = 16) (34%)

Al-Saidi et al. 2002 N = 28

Candidiasis Pulmonary aspergillosis Infective endocarditis

Class I n = 1 (3.5%)

Systemic aspergillosis (1)

Adenovirus, with no GVHD

Class II n = 2 (7.1%)

Severe GVHD (1)

Adenovirus hepatitis

Hemorrhagic cecal perforation (1)

Relapse of myelodysplasia

Non infective endocarditis (1)

Acetaminophen overdose

Spinal cord demyelination (1)

Sepsis with multi-organ failure

CMV pneumonitis (1)

Disseminated Aspergillosis

Bacterial infections (3)

Gut perforation

 oagulase-negative C staphylococcus catheter infection (1)

Pneumonia

Class III n = 6 (21.4%)

Class IV n = 1 (3.5%)

Candida pneumonia Myelodysplasia relapse

Pastores et al. 2007 N = 86 Class I discrepancies n = 15 (17.4%)

Opportunistic infections n = 10

 MV adrenalitis; no C lymphoma

VRE pneumonia

Typhlitis relapse leukemia

Legionella pneumonia

Pulmonary lymphoma

PCP pneumonia

Radiation pneumonia

Invasive aspergillosis Candida empyema

Class II (n = 14) (30%)

 neumonia; cerebral P hemorrhage

 aricella-zoster V meningoencephalitis

Diffuse alveolar damage

HSV esophagitis

Congenital absence of kidney

CMV pneumonia

No pneumonia

 isseminated necrotizing D toxoplasmosis

No pneumonia; renal abscess  o pneumonia; subarachnoid N hemorrhage

Cardiac complications n = 5 Ischemic cardiomyopathy (2)

 o pneumonia; cerebellar N hemorrhage

Thrombotic endocarditis (2) Congestive heart failure (1) Class II discrepancies n = 10 (11.6%)

 erebral and pulmonary C aspergillosis

 emochromatosis and diffuse H alveolar damage

Opportunistic infections n = 3

Idiopathic hepatitis

Candidemia

Normal colon

VRE meningitis

Pulmonary fibrosis

CMV proctitis

Sepsis

 ardiopulmonary complications C n = 7

Cholestatic liver disease

Pulmonary embolism (4)

Xavier et al. (2005) n = 544

Thrombotic endocarditis (2)

Class I (8.6%)

Pulmonary hemorrhage (1)

Hematological disease – 15 Pneumonia – 5

20  What Has Been Learned from Postmortem Studies? Table 20.2  (continued) Gastrointestinal hemorrhage, – 3 Congestive heart failure – 2 Acute pancreatitis – 2 Pulmonary embolism – 2 I nvasive pulmonary aspergillosis – 2 Pulmonary edema – 2 Class II (8.4%)

Pneumonia – 9 Hematological disease – 5

251

significant concordance between the clinical and postmortem diagnoses in 28 critically ill HSCT patients [15]. Ten (36%) of the twenty eight patients had discrepancies uncovered on autopsy; only two discrepancies would have influenced patient management, and none would have altered patient outcome. Most of the unexpected diagnoses were infections, and the rest included non-infective endocarditis, GVHD, and gastrointestinal and neurologic diagnoses. The authors concluded that clinical diagnosis alone might be appropriate for withdrawal of care decision-making in these patients.

I nvasive pulmonary aspergillosis – 5 Pulmonary hemorrhage – 4 Other forms of aspergillosis – 2

20.5 Summary

Pulmonary candidiasis – 2 Class III (18.7%)

Hemosiderosis – 17  econdary malignant neoplasm of S kidney and renal pelvis – 9  leural effusion in conditions P classified elsewhere – 9  econdary malignant neoplasm S of other unspecified digestive organ – 5 Pulmonary hemorrhage – 4

Class IV (20.2%)

Pulmonary hemorrhage – 14 Pulmonary edema – 8 Gastrointestinal hemorrhage – 7  ontraumatic intracerebral N hemorrhage – 6  leural effusion in conditions P classified elsewhere – 6  econdary malignant lung S neoplasm – 5

Infectious and noninfectious pulmonary diseases are commonly found on postmortem autopsy studies in patients with hematological malignancy and HSCT recipients. Despite the technological advances in diagnostic testing and imaging modalities, obtaining an accurate clinical diagnosis remains difficult and is often not possible until autopsy. Major diagnostic discrepancies between clinical premortem diagnoses and postmortem autopsy findings have been reported in patients with hematologic malignancy. The most common missed diagnoses are due to opportunistic infections and cardiopulmonary complications. These findings underscore the importance of enhanced surveillance, monitoring, and treatment of infections and cardiopulmonary disorders in these patients. Autopsies remain important in determining an accurate cause of death and for improved understanding of diagnostic deficiencies, as well as for medical education and quality assurance.

 hronic tubulo-interstitial C nephritis – 5 The Goldman classification of diagnostic discrepancies was applied. Major discrepancies included two categories (class I referred to missed diagnoses that would have led to a change in management with possible increased survival or cure; class II referred to major missed diagnoses that would not have impacted survival because no treatment was available, treatment was given even though the diagnoses was unknown, or the patient refused further treatment). Minor discrepancies included two categories (class III referred to missed minor diagnoses related to the terminal disease process but not directly related to the cause of death, and class IV referred to missed minor diagnoses that did not contribute to the cause of death but ultimately may have been significant had the patient survived the major illness)

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253 Nebraska Medical Center Bone Marrow Transplant Group. Am J Med 96:327–334 54. Pastores S, Papadopoulos E, Voigt L et  al (2003) Diffuse alveolar hemorrhage after allogeneic hematopoietic stemcell transplantation: treatment with recombinant factor VIIa. Chest 124:2400–2403 55. Wanko S, Broadwater G, Folz R et  al (2006) Diffuse alveolar hemorrhage: retrospective review of clinical outcome in allogeneic transplant recipients treated with aminocaproic acid. Biol Blood Marrow Transplant 12: 949–953 56. Costa MBG, Siqueira SAC, Saldiva PHN et  al (2004) Histologic patterns of lung infiltration of B-cell, T-cell, and Hodgkin lymphomas. Am J Clin Pathol 121:718–726 57. Kaminsky DA, Hurwitz CG, Olmstead JI (2000) Pulmonary leukostasis mimicking pulmonary embolism. Leuk Res 24:175–178 58. Murase T, Yamaguchi M, Suzuki R et al (2007) Intravascular large B-cell lymphoma (IVLBCL): a clinicopathologic study of 96 cases with special reference to the immunophenotypic heterogeneity of CD5. Blood 109:478–485 59. Kitanaka A, Kubota Y, Imataki O et al (2009) Intravascular large B-cell lymphoma with FDG accumulation in the lung lacking CT/(67)gallium scintigraphy abnormality. Hematol Oncol 27:46–49 60. Needleman SW, Stein MN, Hoak JC (1981) Pulmonary embolism in patients with acute leukemia and severe thrombocytopenia. Western J Med 135:9–13 61. Daniels C, Myers J, Utz J et al (2007) Organizing pneumonia in patients with hematologic malignancies: a steroidresponsive lesion. Respir Med 101:162–168 62. Mokhtari M, Bach PB, Tietjen PA et al (2002) Bronchiolitis obliterans organizing pneumonia in cancer: a case series. Respir Med 96:280–286 63. Lee S, Park J-J, Sung S et  al (2009) Acute fibrinous and organizing pneumonia following hematopoietic stem cell transplantation. Korean J Intern Med 24:156–159 64. Paz HL, Crilley P, Patchefsky A et al (1992) Bronchiolitis obliterans after autologous bone marrow transplantation. Chest 101:775–778 65. Gutman JA, Allen CT, Madtes DK et al (2008) Pulmo­nary veno-occlusive disease following reduced-intensity cord blood transplantation. Bone Marrow Transplant 42: 559–561 66. Hackman RC, Madtes DK, Petersen FB et  al (1989) Pulmonary venoocclusive disease following bone marrow transplantation. Transplantation 47:989–992 67. Kuga T, Kohda K, Hirayama Y et al (1996) Pulmonary venoocclusive disease accompanied by microangiopathic hemolytic anemia 1 year after a second bone marrow transplantation for acute lymphoblastic leukemia. Int J Hematol 64: 143–150 68. Mukai M, Kondo M, Bohgaki T et  al (2003) Pulmonary veno-occlusive disease following allogeneic peripheral blood stem cell transplantation for chronic myeloid leukaemia. Br J Haematol 123:1 69. Troussard X, Bernaudin JF, Cordonnier C et  al (1984) Pulmonary veno-occlusive disease after bone marrow transplantation. Thorax 39:956–957 70. Williams LM, Fussell S, Veith RW et al (1996) Pulmonary veno-occlusive disease in an adult following bone marrow

254 transplantation. Case report and review of the literature. Chest 109:1388–1391 71. Mandel J, Mark EJ, Hales CA (2000) Pulmonary venoocclusive disease. Am J Respir Crit Care Med 162: 1964–1973 72. Bunte MC, Patnaik MM, Pritzker MR et al (2008) Pulmonary veno-occlusive disease following hematopoietic stem cell transplantation: a rare model of endothelial dysfunction. Bone Marrow Transplant 41:677–686 73. Cordonnier C, Fleury-Feith J, Escudier E et  al (1994) Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients. Am J Respir Crit Care Med 149:788–794 74. Kajiume T, Yoshimi S, Nagita A et al (1999) A case of myelodysplastic syndrome complicated by pulmonary alveolar proteinosis with a high serum KL-6 level. Pediatr Hematol Oncol 16:367–371 75. Watanabe K, Sueishi K, Tanaka K et al (1990) Pulmonary alveolar proteinosis and disseminated atypical mycobacteriosis in a patient with busulfan lung. Acta Pathol Jpn 40: 63–66 76. Kohno N, Inoue Y, Hamada H et  al (1994) Difference in sero-diagnostic values among KL-6-associated mucins ­classified as cluster 9. Int J Cancer Suppl 8:81–83 77. Gerain J, Sculier JP, Malengreaux A et al (1990) Causes of deaths in an oncologic intensive care unit: a clinical and

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Part Lung Infections in Patients with HM

IV

 

Common Viral Pneumonia

21

David Schnell, Jérôme Legoff, and Élie Azoulay

Contents 21.1 Introduction............................................................. 257 21.2 Common Respiratory Viruses............................... 257 21.3 Epidemiology........................................................... 258 21.4 Clinical Manifestations........................................... 260 21.5 Diagnosis.................................................................. 263 21.5.1 Antiviral Treatment................................................... 265 21.6 Prevention................................................................ 267 21.7 Conclusion............................................................... 268 References............................................................................ 268

21.1 Introduction Common respiratory viruses are probably among the leading causes of community-acquired pneumonia [1, 2] but, oddly enough, have long been underrecognised in patients with haematologic malignancies (HMs), perhaps in part due to the lack of rapid and sensitive diagnostic methods and of effective treatments. Over the last 2 decades, the expanding use of high-dose chemotherapy and haematopoietic stem cell transplantation (HSCT) in various malignancies has improved the prognosis of patients with HMs at the cost of increased opportunities for severe infections [3–5]. Combined with the development of new diagnostic methods and introduction of antiviral drugs, this increased infection rate has rekindled interest in the effects of common respiratory viruses in patients with HMs. These viruses are now recognised as true opportunistic respiratory pathogens in immunocompromised hosts.

21.2 Common Respiratory Viruses D. Schnell Hôpital Saint Louis, Service de Réanimation médicale, Université Denis Diderot, 1 avenue Claude Vellefaux, 75010 Paris Cedex, France J. Legoff Hôpital Saint Louis, Laboratoire de Virologie, Université Denis Diderot, 1 avenue Claude Vellefaux, 75010 Paris Cedex, France É. Azoulay (*) Service de Réanimation Médicale, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010, Paris, France and Medical Intensive Care Units, Saint-Louis Hospital, Paris 7 University, Paris, France e-mail: [email protected]

There is no clear definition of common respiratory virus. Viruses that consistently produce respiratory manifestations are considered respiratory viruses. These include members of the following families of RNA viruses: Orthomyxoviridae (human influenza viruses), Paramyxoviridae (respiratory syncytial virus [RSV], parainfluenza viruses [PIV], and human metapneumoviruses [MPV]), Coronaviridae (human respiratory coronaviruses), and Picornaviridae (human rhinoviruses). Other viruses that cause respiratory manifestations in many, but not all, patients are con­sidered respiratory viruses because they are often associated

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_21, © Springer-Verlag Berlin Heidelberg 2011

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with seasonal respiratory events. Examples include Adenoviridae (adenoviruses) and some Picornaviridae (non-poliomyelitic enteroviruses). A separate chapter of this book focuses on newly discovered and emerging respiratory viruses (avian influenza viruses, newly discovered coronaviruses, polyomaviruses KI and WU, human bocavirus, and mimivirus). CMV and Herpes pneumonia will also be addressed by Dr. Chemaly and colleagues in two different chapters in this book. Human influenza viruses are enveloped, negativesense, single-stranded RNA viruses. They are classified into three antigenic types, A, B, and C [6]. The envelope of influenza A and B viruses carries two major antigenic proteins, haemagglutinin (HA) and neuraminidase (NA). HA allows the virus to bind to sialic acid-conjugated glycoproteins at the surface of respiratory epithelium cells. NA plays a crucial role in viral dissemination by releasing newly formed virions from host cells. The influenza C envelope supports a unique protein sharing the properties of both HA and NA and known as haemagglutinin-esterase-fusion factor [6]. Influenza B and C viruses can infect humans and some mammalian species, whereas influenza A also infects most avian species [6]. RSV and PIV types 1–4 are enveloped, negativesense, single-stranded RNA viruses. RSV belongs to the Paramyxovirus genus, and PIV 1–4 to the Pneumovirus genus, of the Paramyxoviridae family [7]. Their envelopes support two major antigenic surface proteins, one for binding and one for fusion to the cell membrane. Attachment to host cell receptors is mediated by the G protein of RSV and by a haemagglutinin neuraminidase for PIV [7, 8]. The fusion protein F is common to both genera and allows the virus to penetrate within the host cells after binding [8]. Antigenic variations in the G protein determine two major RSV groups, A and B. Antigenic variations also occur in PIV but have less immunological impact [7]. The natural hosts of RSV are humans and chimpanzees, whereas PIV infects only humans [9, 10]. Human MPV is a recently discovered virus belonging to the Paramyxoviridae family [11]. The human MPV genome and structure are very similar to those of RSV, and both viruses display the same surface proteins [12]. Available data indicate that human MPV infects only humans, although this virus is believed to originate from birds [13]. Human rhinoviruses and non-poliomyelitic enteroviruses are non-enveloped, single-stranded RNA viruses belonging to the Picornaviridae family. The

D. Schnell et al.

Rhinovirus genus consists of more than 100 different serotypes divided into three species (A, B, and the newly described C species) based on antigenic variations in the three proteins VP1, VP2, and VP3 found on the capsid surface [14, 15]. Enteroviruses are divided into four species (A, B, C, and D) [16, 17]. They share the same structure as other Picornaviridae. Humans are the only natural host of these viruses [14, 16]. Coronaviruses are enveloped, positive-sense, singlestranded RNA viruses belonging to the Coronaviridae family [18]. Their envelope supports two main proteins, the haemagglutinin-esterase protein and the antigenic protein S [18]. Human coronaviruses 229E and OC43 were the predominant human respiratory coronavirus strains before the recent identification of the new human coronaviruses NL63, HKU1, and SARS [19–21]. Adenoviruses are non-enveloped, double-stranded DNA viruses that form the Adenoviridae family. Six subgenera (A–F) and 51 human serotypes of adenoviruses have been described [22]. Adenoviruses have an icosahedral capsid made of 250 protein subunits called capsomeres [23]. Humans are the only natural hosts of these viruses.

21.3 Epidemiology Common respiratory viruses are ubiquitous pathogens that share a number of epidemiological features. Most of them are responsible for outbreaks that occur with a remarkable seasonal pattern. These seasonal variations in viral activity occur only in temperate climates and tend to disappear in equatorial zones. This phenomenon is incompletely understood and may involve not only specific viral characteristics, but also seasonal changes in living conditions [6]. Influenza, RSV, human MPV, and Coronavirus activities peak during the winter months [6, 7, 18]. PIV1 and 2 cause outbreaks in the fall [7]. Seasonality is less pronounced for PIV3 and Picornaviridae, which exhibit year-round activity with peaks in the spring for PIV3, spring and fall for human rhinoviruses, and summer and fall for non-poliomyelitic Enteroviruses [7, 14, 16]. Little is known about the epidemiology of PIV4, since this virus is responsible for mild infections and is therefore rarely identified [7]. Common respiratory viruses typically cause infections in early childhood. Influenza C usually causes

21  Common Viral Pneumonia

mild infections that lead to the acquisition of protective antibodies capable of preventing recurrences [24]. Influenza A and B are considerably more common and can cause disease of greater severity, most notably in high-risk groups, such as elderly people and patients with chronic respiratory or cardiovascular conditions, chronic renal failure, diabetes mellitus, or immune deficiencies [6]. It is estimated that about 5% of adults and 20% of children experience an influenza episode every year throughout the world [25]. Although most influenza episodes are mild, the high occurrence rate results in a huge burden of disease that has a severe socioeconomic impact [6]. Influenza viruses are believed to be the seventh cause of death in the USA [26]. Influenza A and B infections start in childhood and continue to occur throughout the life span, because antigenic variations affecting HA and, to a lesser extent NA, hamper the acquisition of protective immunity. Two mechanisms of antigenic variations have been described, antigenic drift and antigenic shift [6]. Antigenic drift probably results from the accumulation of point mutations that occur continuously in influenza viruses, with new variants appearing annually or every few years. These new variants replace pre-existing ones by immunological selection and are only incompletely recognised by immunity resulting from exposure to earlier strains. Antigenic shift is a considerably rarer event that occurs only in influenza A and results in a virus with a completely new HA or NA [6]. The result is an influenza pandemic due to the absence of protective immunity against the new virus. Progressive acquisition of immunity against this new strain attenuates the intensity of the epidemic over the following years. The exact genetic mechanisms of antigenic shift are incompletely known, and the emergence of pandemic strains is not predictable. Pandemic strains originate from the recombination of influenza strains circulating in different animal species, including birds, pigs, and humans [6]. Five pandemics occurred in the twentieth century, and the 2009 “Mexican flu” pandemic due to the new H1N1 influenza virus is the first pandemic in the twenty-first century [6, 27]. RSV and PIV are typically infections of early childhood [7]. RSV and, to a lesser extent, PIV also undergo antigenic changes that lead to recurrences throughout the life span. These recurrences may be severe, especially in patients with chronic respiratory conditions and in the elderly. The burden of RSV-related diseases may be comparable to that of influenza [28].

259

Few data are available on the specific epidemiological characteristics of common respiratory viruses in patients with HMs. Reported incidence rates vary widely, from 1.8% to 30% [29, 30]. This variability may be explained by disparities in the type of patients enrolled, reasons for screening patients for respiratory viruses and, most importantly, diagnostic methods used. Whatever the exact incidence, one can reasonably assume that attack rates of common respiratory viruses in immunocompromised patients are closely related to the prevalence of respiratory viruses in the community, which serves as the viral reservoir for immunocompromised patients [31]. This has been confirmed in recent studies showing that the occurrence of viral respiratory diseases in the enrolled immunocompromised patients paralleled the concomitant viral activity in the community [32, 33]. Accordingly, influenza viruses and RSV are the viruses most commonly identified in the largest cohorts of HM patients, each accounting for about one-third of viral respiratory events [34–36]. PIV, Picornaviridae, and adenoviruses come next. It must be pointed out that influenza viruses accounted for a much higher proportion (up to 75%) of viral respiratory events in the study by Martino et al. conducted in the setting of a major influenza outbreak in the community [32]. Adenovirus epidemiology in patients with HM deserves special attention. Similar to other common respiratory viruses, adenoviruses cause primary infections in childhood, usually during the first few years of life. Adenoviruses may account for 5% to 10% of viral respiratory infections in children [23], and also cause outbreaks in closed and semi-closed populations of young adults such as the military [37, 38]. A distinctive feature of adenoviruses is the ability to cause chronic latent infection by persisting in lymphoepithelial tissues, most notably in the nasopharynx [23]. The epidemiology of adenoviruses in patients with HM has not been the focus of specific studies. Nevertheless, exogenous contamination, by the respiratory or orofaecal route, may be less important than reactivation of the latent virus [39]. Thus, adenoviral infections in patients with HM may be related chiefly to the level of immunosuppression and, perhaps, to unknown viral factors driving reactivation, rather than to the level of viral activity in the community. The epidemiologic characteristics of influenza, RSV, and PIV are particularly well known, perhaps in part because infections with these viruses are considerably more common compared to those due to other

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viruses. However, the availability of simple and rapid diagnostic tools for these three viruses probably played a great role. Since Picornaviridae, Coronaviridae, and the newly discovered human MPV are mainly diagnosed using reverse-transcriptase polymerasechain-reaction technology (rt-PCR), data on their epidemiology are still limited. Recent studies using rtPCR detection of respiratory viruses in patients with HM revealed a high incidence of human MPV infections, similar to that of RSV infections [30, 36]. In the near future, studies using molecular biology tools may help to clarify the epidemiology of common respiratory viruses and may lead to a radical change in current concepts.

21.4 Clinical Manifestations Common respiratory virus infections have been studied chiefly in patients receiving high-dose chemotherapy and haematopoietic stem cell transplantation (HSCT). Compared with immunocompetent patients, several distinctive features have been reported. Viral shedding lasts longer and progression to pneumonia is more common [31]. Late airflow obstruction has been reported in HSCT recipients [40]. Some respiratory viruses are responsible for extra-respiratory manifestations. Although rare in immunocompetent hosts, these manifestations might be more common in patients with HM. Common respiratory viral infections in patients with HM are characterized by prolonged viral shedding. A median duration of 2 weeks was found in most studies [30, 32, 33, 36]. However, viral shedding may last for months in some cases [41, 42]. In addition, the amount of virus shed per day may be greater in HM patients than in immunocompetent individuals [43]. Similarly to findings in immunocompromised patients, children shed more viruses over a longer period than do adults [31]. This prolonged high-load viral shedding is of critical importance, since it may enhance both viral dissemination [43, 44] and the emergence of resistant strains via prolonged exposure to antiviral drugs [41, 42]. As stated above, common respiratory viruses have long been underrecognised in patients with HM. In the 1990s, the first reports of common respiratory virus infections focused on influenza and RSV [45–50]. In

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these studies, progression to pneumonia occurred in about 75% of patients infected with influenza viruses and 50% of those infected with RSV, and was associated with mortality rates of 25% for influenza and about 80% for RSV. One possible explanation for these striking observations may be a surge of interest in respiratory viral infections in HM patients that led to the publication of the most severe cases. Not surprisingly, these studies had small numbers of patients and high rates of nosocomial infections. More recently, studies of large patient cohorts led to better characterization of influenza-related pneumonia in patients with HM [29, 32–34]. About one-third of patients develop lower respiratory tract infection (LRTI). Although less common than in previous reports, influenza-related pneumonia remains a severe condition with a 15–30% mortality rate. As in immunocompetent hosts, upper respiratory tract infection (URTI) is almost always present and often precedes LRTI [32, 49, 51, 52]. URTI can be considered a useful argument supporting the diagnosis of respiratory viral infection in patients with HM investigated for pneumonia [53]. However, the identification of a common respiratory virus does not exclude an associated bacterial or fungal infection. These co-infections are very frequent, occurring in 12–25% of cases of influenzarelated pneumonia [32, 34, 50]. There are no reports of extra-respiratory manifestations in patients with HM, although myocarditis, pericarditis, myositis, meningoencephalitis, Guillain-Barré syndrome, and Reye syndrome have been described in immunocompetent patients [6, 54]. RSV-related pneumonia is now believed to complicate about 30–40% of RSV infections in patients with HM [32, 34, 47]. Again, mortality remains high, ranging from 15% to 30%. URTI is a common clinical manifestation. No clear data on the incidence of concomitant bacterial or fungal infections are available in the literature, and RSV-related pneumonia in patients with HM are often ascribed to viral infection [53]. However, bacterial co-infections were present in as many as 30% of patients in a large study of RSV infections in immunocompetent individuals [55]. Bacterial or fungal co-infection may be more common in patients with HM and must be carefully sought. Nonsustained viraemia may accompany RSV infection, and RSV was associated with cardiac arrhythmias and neurological disorders in two case reports [8, 56]. However, no extra-respiratory manifestations of RSV

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infection have been described in immunocompromised patients. PIV infections have also been studied in patients with HM [34, 57]. PIV type 3 was the cause in 90% of reported cases. In these studies, PIV-related pneumonia was comparable to influenza-related pneumonia, with about one third of patients being affected, a high rate of concomitant URTI, and a 15–30% mortality rate. Co-infections were found in as many as 53% of the patients studied by Nichols et al. [57]. However, in a recent study using rt-PCR for routine respiratory virus detection in HSCT recipients, PIV was found in respiratory samples of asymptomatic patients [30], whereas influenza, RSV, and human MPV were not detected. This finding suggests that studies using conventional diagnostic methods may have overestimated the true severity of PIV in patients with HM. Some reports suggested a role for PIV3 in the occurrence of neurologic manifestations (such as meningitis, encephalitis, and Guillain-Barré syndrome) and myocarditis [58]. Such manifestations have not been reported in immunocompromised patients. Case reports suggest that the recently discovered human MPV may induce severe pneumonia in patients with HM [59–61]. To our knowledge, two retrospective cohorts [62, 63] and three prospective cohorts [30, 36, 64] describing human MPV infections in patients with HM have been published. The small number of patients and highly variable results (pneumonia in 0–43% of patients with a 0–40% mortality rate) preclude definitive conclusions about human MPV-related pneumonia in patients with HM. Although debated, the occurrence of asymptomatic viral shedding may suggest lesser severity of human MPV-related pneumonia compared to influenza and RSV [30, 65]. Two cases of encephalitis with human MPV detected in

cerebrospinal fluid in immunocompetent paediatric patients have been published [66, 67]. No extra-respiratory manifestations have been reported in patients with HM. Since the identification of Picornaviridae and Coronaviridae relies chiefly on molecular biology tools, only limited data are available about their contribution to respiratory viral infections in patients with HM. Epidemiological evidence supports an association of human rhinovirus with LRTI in immunocompetent children and elderly people [68, 69]. Despite growing evidence that human rhinovirus is able to replicate in lower respiratory tract cells in vitro and in vivo [70, 71], whether this virus can cause pneumonia remains debated [72]. Several reports in patients with HM link human rhinovirus to LRTI [73–77]. However, these retrospective studies in small patient populations with high rates of pulmonary co-pathogen identification fail to demonstrate a clear role for human rhinovirus in the development of pneumonia. Non-poliomyelitic enteroviruses are chiefly responsible for URTI [16]. Only a few studies with small numbers of patients have focused on these viruses in patients with HM, and no conclusions can be drawn from their results [77–80]. Coronaviridae are also principally responsible for URTI but may occasionally cause pneumonia [81]. No studies have evaluated the role of Coronaviridae in patients with HM, and only two case reports have been published [82, 83]. Although it is now clear that most of the common respiratory viruses are responsible for an increased rate of pneumonia in patients with HM (Table  21.1 and Fig. 21.1–21.3), the exact nature and causative mechanisms of pneumonia in this situation remain unknown. The only risk factor for virus-related pneumonia found consistently in studies is lymphocytopenia, defined

Table  21.1  Clinical manifestations of influenza, respiratory syncytial virus (RSV), parainfluenza virus (PIV), human metapneumovirus (hMPV), and adenovirus in patients with haematological malignancies Influenza RSV PIV hMPV Adenovirus Pneumonia rate (%)

33

30–40

Up to 30a

Up to 40a

NA

Coinfection rate (%)

12–25

NA

Up to 50

NA

50

Mortality rate (%)

15–30

15–30

15–30

Up to 40

Asymptomatic shedding

No

No

Yes

Yes

a

a

a

NA not available The occurrence of asymptomatic viral shedding may indicate lesser severity than previously thought

a

50–80 No

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Fig.  21.1  Diffuse alveolo-interstitial pneumonia in a PIV3infected patient

Fig.  21.2  Diffuse alveolar consolidations in a patient coinfected with influenza and Streptococcus pneumoniae

using a variety of cutoffs [29, 32–34]. One study found that lymphocytopenia (absolute lymphocyte count less than 200 cells/mL) was independently associated with mortality in patients with influenza-related pneumonia [34]. A higher incidence and greater severity of virusrelated pneumonia have been noted in HSCT recipients compared with other patients with HM. This finding may reflect deeper lymphocyte depletion. However, in a study by Martino et al., pneumonia rates were comparable in patients with and without lymphocytopenia [32]. The possible higher incidence and greater severity

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Fig.  21.3  Thoracic CT scan showing bronchiolitis pattern (bronchial wall thickening associated with ground-glass attenuation, interlobular septa thickening and tree-in-bud opacities) in an influenza-infected patient

of virus-related pneumonia within the first few days after HSCT, compared with infections occurring later on, may reflect deeper lymphocyte depletion [53]. A similar mechanism may underlie the surprising protective effect of corticosteroid therapy in the study by Nichols et  al., since this treatment is often given to treat graft-versus-host disease (GVHD) after lymphoid engraftment [33]. Common respiratory viruses increase mortality in patients with HM mainly by causing severe pneumonia, but they may also contribute to a long-term decline in pulmonary function. RSV, PIV, and influenza infections have been linked to late airflow obstruction in HSCT recipients [40]. In a study focusing specifically on the role of respiratory viruses in late airflow obstruction, PIV LRTI was the strongest risk factor, followed by PIV URTI [84]. Pneumonia caused by RSV was a borderline-significant risk factor. The exact causative mechanisms remain unknown, but inflammation resulting from prolonged viral persistence and pneumoniainduced post-acute-phase inflammation have been suggested as possible factors [84, 85]. A distinctive feature of adenoviruses in HM patients is that they may either be acquired via exogenous respiratory or oro-faecal contamination, or arise via reactivation of latent viruses [39, 86]. Adenoviruses cause a wide spectrum of clinical manifestations ranging from benign conjunctivitis to rapidly fatal disseminated disease. In patients with HM, the risk of severe adenoviral

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disease seems related to the level of immunosuppression. Adenoviral disease has been reported in 3–27% of HSCT recipients within the first 100  days after transplantation [87–89]. Higher rates may occur in paediatric patients compared with adults [88, 90]. In vivo and ex vivo graft T-cell depletion [86, 87, 91], lymphocytopenia [86], GVHD [87, 89], viral shedding from more than one site [86, 88, 90], and adenovirus viraemia [86, 92–94] have been reported as risk factors for severe adenoviral disease. Adenovirus viraemia consistently preceded viral shedding from more than one site in the study by Chakrabarti et al. [86]. This risk factor is of critical importance since it guides pre-emptive antiviral therapy. Adenoviral disease has been chiefly reported in myeloablative HSCT recipients, but has also been described in non-myeloablative HSCT recipients, autologous transplant recipients, and patients with chronic lymphocytic leukaemia treated with fludarabine combined with CD52 monoclonal antibodies [88, 89]. In allogeneic transplant recipients, the most frequent manifestations of adenoviral infection are gastrointestinal disease and haemorrhagic cystitis [95, 96]. Although haemorrhagic cystitis is a benign localised event, it is associated with high morbidity [90]. It must be pointed out that in a patient with febrile haematuria and adenovirus urinary excretion, the onset of acute renal failure with flank pain may reveal adenovirus nephritis [97]. Gastrointestinal manifestations include gastroenteritis and colitis, which often manifest as febrile haemorrhagic diarrhoea [95, 98]. The most severe manifestations of adenoviral infection are hepatitis, encephalitis, and pneumonia [86, 89, 90]. Adenovirus-related pneumonia occurred in 15 of the 85 patients with adenovirus infection in the study by La Rosa et al. [89]. The pneumonia was isolated in 11 patients and a manifestation of

Table 21.2  Methods for detecting common respiratory viruses Test Sensitivity Specificity

disseminated disease in 4 patients. Bacterial and fungal co-infections were found in 50% of patients, in keeping with other studies [90]. The mortality rate was 73% overall, 50% in patients with isolated pneumonia, and 80% in patients with disseminated disease [89].

21.5 Diagnosis Respiratory viral infections are the second most common cause of community-acquired pneumonia [2, 99]. They were long considered a simple differential diagnosis, without practical consequences for the patient. Recently, however, the diagnosis of viral respiratory infection has become increasingly relevant for medical care [100, 101]. First, RSV, influenza, PIV, and adenoviruses have been identified as significant causes of community-acquired and nosocomial respiratory infections [29, 102]. Second, new nucleic acid-based assays have been shown to be more sensitive than conventional techniques. Third, specific antiviral drugs are now available for some respiratory viruses, including influenza and adenovirus. Several diagnostic tests have been introduced for the detection of respiratory viruses. The main characteristics of the most widely used assays are shown in Table 21.2. High-quality clinical specimens are needed to ensure the accurate detection of respiratory viruses. Indeed, respiratory virus detection requires a large number of epithelial cells, since viruses are intracellular pathogens. Nasopharyngeal aspirates and nasopharyngeal washes are recognised to be superior to other sample types for detecting respiratory viruses [103, 104]. Because the collection process is unpleasant and

Time to result

Viral targets

Cost

Immunofluorescence staining

++

++

<3 h

<8

15–25 Euros

Rapid antigen testing (immunochromatography)

+

+/++

<1 h

Only available for influenza and RSV

10–15 Euros per test

Cell culture

+

+++

Days to weeks

Depending on the cell lines used

NA

Monoplex NASBA or real-time PCR assay

+++

+++

<12 h

1 or 2 per reaction

10–20 Euros per target

Multiplex molecular assay

+++

++/+++

6 h–24 h

12–20 per reaction in 1 or 2 tubes

50–80 Euros per panel

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time-consuming, causes patient discomfort, and requires a suction device, flocked swabs were recently introduced for respiratory sample collection. Flocked swabs were found to improve the collection and release of epithelial cells [105, 106], and were recently recommended for the diagnosis of the new pandemic H1N1 influenza strain. The number of cells collected is lower with flocked swabs than with nasopharyngeal aspirates, but seems sufficient for respiratory virus detection by immunofluorescence [105, 106]. Flocked swab collection is sensitive, specific, easy to use, and better tolerated by patients, and may therefore constitute a good alternative to nasopharyngeal aspiration. Because most respiratory viruses have high replication rates in the upper respiratory tract, nasopharyngeal secretions are usually sufficient to diagnose respiratory viral infections. However, asymptomatic respiratory virus shedding in the upper respiratory tract may occur even in immunocompromised patients, and URTI may be followed by LRTI, particularly during influenza infections. Thus, virus detection in lungs via bronchoalveolar lavage may be useful to assess the causative role for the virus. Over the past 2 decades, virus isolation and antigen detection have been the mainstay of clinical laboratory testing for respiratory virus infections. Virus isolation required several cell lines and was mainly performed on shell vial cultures. The diagnosis was based on the presence of the cytopathic effect, which requires several days or weeks to develop. To shorten the time to diagnosis, specific monoclonal antibodies were introduced to enable the detection of specific viral antigens within 1–2  days. Direct or indirect fluorescent antibody staining of cells from respiratory specimens (mainly nasopharyngeal swabs or nasopharyngeal aspirates [NPA] and bronchoalveolar lavage fluid) is commonly used to detect viral antigens. In many laboratories, the first-line test is immunofluorescence staining, which requires very little material and provides a result within about 3  h. However commercial monoclonal antibodies are available for a limited number of targets, including influenza A and B; RSV; adenovirus; PIV 1, 2 and 3; and human MPV. Thus, rhinoviruses and coronaviruses, the most frequent causes of URTI and the most recently discovered agents, cannot be detected using monoclonal antibodies. Nucleic acid amplification tests have been proven to be rapid, very sensitive, and specific. The early tests, including PCR, nucleic acid sequence-based

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amplification (NASBA), and real-time PCR assays, were developed in monoplex format. Despite the gain in sensitivity and the ability to test for most respiratory viruses, the need to carry out as many PCR tests as targets has limited the use of this method. None of the current PCR assays has sufficiently high throughput to handle large numbers of samples containing multiple targets. Over the last few years, assays have been introduced in multiplex format. Different technologies have been used. In addition, sensitivities may be lower compared to monoplex real-time RT-PCR. Multiplex PCR procedures are difficult to optimise, because each amplification target corresponds to a set of primers characterized by a unique combination of optimal annealing conditions. Multiple primers included in a single tube may also result in primer-primer interference and in nonspecific nucleic acid amplification. Currently, several multiplex assays can detect up to nine respiratory viruses in a single reaction. Real-time multiplex assays detect up to five targets in a single reaction, depending on the number of channels available in the real-time PCR machine [107–110]. Existing multiplex PCR assays that use agarose gel electrophoresis or capillary electrophoresis as the detection system or multiplex PCR assays combined with an enzyme-linked immunosorbent assay can detect five to nine targets per reaction [111–113]. More recently introduced techniques can detect up to 20 targets in one or two tubes. These include the four techniques detailed below. 1. Low-density micro-array based on cDNA spots that are immobilised on a polymer-coated slide and that hybridise with specific DNA sequences previously amplified from the sample using PCR. Hybridisation is detected based on the production of an insoluble product on the microarray at the sites where amplified DNA products are captured by the probes [114]. 2. Multiplex detection based on Luminex technology. The PCR products are coupled with spectrally distinct fluorescence-labelled micro-beads, which are detected by flow cytometry [115, 116]. 3. Multiplex ligation-dependent probe amplification (MLPA) involves specific viral amplification followed by amplification after hybridisation and binding of virus-specific probes to the PCR product. Identification is accomplished by PCR fragment size analysis using gel electrophoresis methods [117, 118].

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4. Mass spectrometry assays for respiratory virus detection are based on the analysis of base compositions in RT-PCR amplicons [119]. Most assays exhibited specificities comparable to those of cell culture and monoplex real-time reverse transcription (RT)-PCR, and sensitivities similar to those of monoplex (RT)-PCR assays. Although molecular assays, particularly RT-PCR, provide same-day results, they require a nucleic acid extraction step. This step increases the time to results compared to antigen detection by fluorescent staining. Molecular assays should be performed as often as possible to improve patient care by shortening the hospital stay, curtailing or preventing antibiotic therapy, preventing nosocomial spread, and allowing specific antiviral therapy. Therefore, and given the cost of the equipment needed (RT-PCR machine, sequencer, luminex, nucleic acid extractor, DNA chip reader, mass spectrometer), molecular assays will probably be chiefly performed in laboratories receiving large numbers of samples per day. Few data are available on the exhaustive and sensitive detection of respiratory viruses in HM patients. Recent data show that using molecular assays increases the virus detection rate twofold compared to cultures and fourfold compared to immunofluorescence staining [120]. Two prospective studies of molecular assays in

HSCT recipients documented persistent asymptomatic respiratory shedding of PIV and human MPV [30, 65]. These data emphasise the need for prospective studies of the molecular detection of respiratory viruses to elucidate factors associated with symptomatic or asymptomatic respiratory viral infection and to help in the interpretation of positive assays in HM patients.

21.5.1 Antiviral Treatment A chapter from Dr. Sandherr is dedicated to antiviral therapy in this book. Regarding common viruses, we will briefly describe available treatments on influenza and RSV. Two classes of antiviral drugs are available for the treatment of influenza: M2 ion channel inhibitors and neuraminidase inhibitors. The M2 ion channel inhibitors, amantadine and rimantadine, act by inhibiting the M2 protein needed for viral RNA release within the host cells. They are active only against influenza A strains. Their clinical effect is limited, being not significantly different from that of a placebo [121], and is further hampered by the worldwide emergence of resistant influenza A strains [122]. The neuraminidase inhibitors (Table  21.3), oral oseltamivir and inhaled zanamivir, are sialic acid analogues that competitively inhibit the influenza neuraminidase. Randomised controlled trials

Table 21.3  Antiviral treatments for common viral pneumonia Oseltamivir Zanamivir

Ribavirin

Cidofovir

Therapeutic class

Neuraminidase inhibitor

Neuraminidase inhibitor

Nucleoside analogue

Nucleoside analogue

Route

Oral

Inhaled

Inhaled

Intravenous

Regimen

75 mg bid

10 mg bid

Up to 2 g tid

5 mg/kg weeklya

Duration

5 days

5 days

10 daysa

Variableb

Side effects

Rash

Rash bronchospasm

Haemolytic anaemiad bronchospasm

Nephrotoxicityc myelosuppression retinitis

Indication

Influenza

Influenza

RSVe

Adenoviruse

Evidence supporting use

Cohort studies

Cohort studies

Cohort studies

Cohort studies

a

NA not available, bid twice daily, tid three times daily The therapeutic regimens are those described in the available literature b Cidofovir is given in a dose of 5 mg/kg weekly for 2 weeks then every 2 weeks according to the clinical response c Hyperhydratation and probenecide may help to prevent cidofovir nephrotoxicity d Haemolytic anaemia may be readily controlled by blood transfusion e These drugs have not been approved by regulating authorities in these indications a

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showed moderate decreases in symptom intensity and duration with both drugs [123–125]. Neuraminidase inhibitors may also limit bacterial super-infection of the lungs [125, 126]. Early administration of these drugs seems mandatory to obtain a clinical benefit [127]. A more recent cohort study suggested a diminution of 15-day mortality with neuraminidase inhibitors [128]. This result must be interpreted with caution, especially given the study design. There is growing concern about the emergence of oseltamivir-resistant influenza A strains [129]. This phenomenon is not surprising given the high mutation rate in the influenza genome. It should lead clinicians to reconsider the indications of neuraminidase inhibitors and their use as monotherapy to treat influenza [130]. No randomised controlled trials have evaluated the efficacy of neuraminidase inhibitors in patients with HM. The apparently lower mortality in descriptive cohort studies compared with historical studies must be interpreted with caution [33–35, 131]. Many of the patients in these cohorts had bacterial and fungal co-infections, whose specific treatment probably contributed to decreasing mortality. Furthermore, the decision to treat patients was left to clinician discretion, which may have introduced a bias toward selection of patients with greater disease severity. Given both the absence of strong evidence supporting beneficial effects of neuraminidase inhibitor therapy and the rapid emergence of resistant strains, we believe that neuraminidase inhibitor therapy cannot be recommended for HM patients with influenza. Randomised controlled trials are needed to determine the efficacy, safety, and ecological impact of neuraminidase inhibitors in these patients. Ribavirin is the only available antiviral drug for Paramyxoviridae infection (Table 21.3). The efficacy of aerosolized ribavirin was variable in uncontrolled cohorts of patients with RSV-related pneumonia [34, 46, 132]. Again, the results must be interpreted with caution. Early ribavirin therapy, introduced before the onset of respiratory failure, seemed associated with lower mortality in the study by Whimbey et al. [132]. This observation led some authors to evaluate preemptive ribavirin therapy, characterised by ribavirin treatment of RSV URTI to prevent progression to pneumonia [133, 134]. The study by Boeckh et al. is the only randomised controlled trial evaluating preemptive ribavirin therapy in patients with RSV infection [133]. Unfortunately, the trial did not enrol a sufficient number of patients to produce conclusions.

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Intravenous ribavirin has also been evaluated and found unhelpful [29, 135]. Combining ribavirin with intravenous immunoglobulins or RSV-specific immunoglobulins produced variable levels of efficacy in cohort studies [35, 132, 136, 137]. Palivizumab, an RSV-specific monoclonal antibody, was evaluated only in a small cohort [138]. In vitro, ribavirin exhibits mild antiviral activity against PIV [58]. No clear efficacy of aerosolized ribavirin was found in small, uncontrolled cohorts of patients with HM [34, 139]. Early initiation of ribavirin therapy has been proposed to enhance efficacy [140]. No studies have evaluated intravenous immunoglobulins or RSV-specific immunoglobulins, which contain high titres of PIV-specific immunoglobulins. An in vitro study suggests that ribavirin may be of interest for treating human MPV-related pneumonia, but this drug has not been evaluated in patients with HM [141]. To date, there is no strong evidence supporting the use of ribavirin, either alone or combined with immunoglobulins, to treat Paramyxoviridae-related pneumonia in patients with HM. No controlled randomised study has evaluated the treatment of adenoviral disease in patients with HM. Ribavirin and cidofovir have been suggested for the treatment of adenoviral infections, but only uncontrolled cohort studies are available to support their use. Intravenous ribavirin therapy failed to demonstrate benefits in available studies [89, 142–147]. Cidofovir therapy (Table  21.3) seemed to result in better outcomes in small, uncontrolled series [148–153]. Ganciclovir and antiretroviral drugs, such as zalcitabine, alovudine, and stavudine, exhibit in vitro activity against adenoviruses, but have not been specifically evaluated in clinical settings [95, 154]. Considering the lack of specific antiviral drugs, decreasing the level of immunosuppression seems to be a rational treatment approach [155]. T-cell therapy has also been reported in some small series [155, 156]. Early cidofovir treatment seems associated with a better outcome [151]. Weekly PCR screening for adenovirus viraemia has been suggested to guide pre-emptive cidofovir therapy [91–94, 153, 157]. The exact threshold above which pre-emptive cidofovir therapy should be initiated is unknown. Randomised controlled trials are needed to better define the optimal viraemia threshold for antiviral therapy and to evaluate the benefits from this treatment.

21  Common Viral Pneumonia

The greater severity of common respiratory viral infections in HM patients and the lack of clearly proven effective antiviral drugs emphasise the critical importance of preventive strategies.

21.6 Prevention The occurrence of common respiratory virus infections in patients with HM is closely related to viral activity in the community. However, nosocomial outbreaks have been described in haematologic wards, often within a few days after an outbreak in the community [31, 43, 44, 46, 158–160]. Preventing nosocomial transmission of common respiratory viruses requires a multifaceted approach (Table 21.4) that targets not only the modes of transmission, but also the source of the viruses [43]. Nosocomial outbreaks are believed to originate from infected patients and from infected health-care workers. Infection control measures include screening symptomatic patients for common respiratory viruses, early isolation of infected patients, screening healthcare workers and visitors for respiratory symptoms, and avoiding contact of symptomatic individuals with patients. Most haematologic wards do not allow Table 21.4  Infection control measures for common respiratory viruses Specific infection control measures   Screening patients for respiratory virus infections  Contact isolation with droplet precautions for infected patients  Screening visitors and healthcare workers for URTI symptoms   Prohibiting visits by individuals with URTI symptoms  Prohibiting work for healthcare workers with URTI symptoms   Prohibiting visits by children Enhanced standard precautions  Reinforced hand hygiene before and after contact with patients Annual influenza immunisation   Patients with HM   Family contacts of patients   Health-care workers

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children to visit patients, as children are highly prone to common respiratory virus infections and may exhibit viral shedding long after symptom resolution [39]. Continual reinforcement of standard hygiene measures, especially hand hygiene before and after contact with patients, is also strongly recommended. Awareness of the usefulness of these measures, and therefore adherence to the measures, are low, but can be enhanced by educational programs [161]. Most of the common respiratory viruses are transmitted by droplets or direct contact of infected secretions with the nasal mucosa or conjunctiva. Indirect transmission via contaminated fomites or devices is also possible, since these viruses may survive several hours on these surfaces [6, 7, 58]. Consequently, contact isolation of infected patients combined with droplet precautions is mandatory [162]. A gown, gloves, and a mask with eye protection must be worn for all contacts with infected patients. Airborne transmission of influenza is suspected [163, 164] but not yet proven, and two recent studies suggest that surgical masks may be as effective in preventing influenza transmission as masks with greater filtration capacity [165, 166]. Infection control measures have not been evaluated in randomised control trials, but a beforeand-after study suggests they may help to prevent the transmission of common respiratory viruses [43]. It must be pointed out that asymptomatic viral shedding, when present, limits the effectiveness of infection control measures [30, 65]. The optimal duration of isolation is unknown. Whether isolation should be prolonged in asymptomatic patients with persistent low-titre viral shedding detected only by molecular methods remains unclear. Since adenovirus acquisition is known to result also from endogenous reactivation, adenoviral infections may be chiefly related to the level of immunosuppression [39, 86] and, therefore, may not be effectively prevented by standard infection control measures. To date, influenza is the only common respiratory virus for which a vaccine is available. Immunisation remains the cornerstone of influenza prevention [6]. The immunogenicity of the inactivated influenza vaccine is lower in patients with HM compared with immunocompetent controls [167–172]. A second dose of influenza vaccine has been proposed to enhance immunogenicity, but this strategy was not beneficial in an open-label randomised study [169, 170]. The timing of influenza immunisation may be important. Immunogenicity may be improved by giving the vaccine at least 6  months after HSCT or at least 7  days

268

after intensive chemotherapy [168, 171]. The efficacy of influenza immunisation has not been evaluated in randomised control trials. However, a retrospective cohort study suggested benefits from influenza immunisation in HSCT recipients [173]. Influenza immunisation appears safe in patients with HM, and lifelong seasonal administration of the influenza vaccine is therefore recommended in these high-risk patients [174]. Importantly, family contacts should be immunised also to prevent transmission within the household. Of critical importance is the issue of health-care worker immunisation, which is known to prevent nosocomial acquisition of the virus [175]. Pharmacological interventions have been proposed to prevent common respiratory virus infections. Intravenous immunoglobulins and palivizumab have been suggested for RSV infection prevention, but have not been evaluated in patients with HM. Prophylactic post-exposure oseltamivir therapy is currently recommended in patients with HM [176]. This preventive measure has not been evaluated in randomised controlled trials, but seems safe based on a recent retrospective study in HSCT recipients [177]. Considering the lack of proven benefits of oseltamivir therapy and the growing concern about the emergence of oseltamivir-resistant influenza strains, oseltamivir therapy should be carefully evaluated before it is suggested for use on a large scale [130]. Another way to prevent morbidity and mortality related to common respiratory viruses in patients with HM is to limit the risk of progression to pneumonia. The pre-emptive treatment of viral URTI has been discussed above. Given the severity of common respiratory virus pneumonia in patients with HM, it appears logical and prudent to postpone HSCT in patients with documented viral infections. A retrospective cohort study suggested that this measure might prevent RSVrelated pneumonia in patients undergoing HSCT [178]. It is unclear whether this measure might be applied to all types of HSCT, to intensive chemotherapy courses, and for all respiratory viruses.

21.7 Conclusion Common respiratory viruses are now recognised as true opportunistic respiratory pathogens in patients with HM. In these patients, they constitute a common

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cause of potentially severe pneumonia. However, areas of uncertainty remain, indicating a need for further investigations. The epidemiology of common respiratory virus infections in patients with HM has not been extensively studied. Large epidemiological studies of common respiratory virus infections in patients with HM based on molecular biology tools may lead to radical changes in knowledge. Although it is now clear that common respiratory viruses are responsible for increased pneumonia rates in patients with HM, the exact nature and causative mechanisms of these pneumonia cases remain unknown. Studies are warranted to investigate the role of viruses in the development of these LRTIs. The virus might directly injure alveolar epithelium or promote lung super-infection by causing bronchial epithelium damage. These studies would also help to determine the potential benefit of pre-emptive or curative antiviral therapy. Finally, randomised controlled studies of antiviral therapy in patients with HM are urgently needed.

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Emerging Viral Infections

22

Oliver Schildgen

Contents 22.1 Introduction............................................................. 275 22.2 Human Metapneumovirus..................................... 275 22.3 Human Bocavirus................................................... 276 22.4 Human Coronaviruses............................................ 278 22.5 Polyomaviruses........................................................ 280 22.6 Picornaviruses......................................................... 281 22.7 Reemerging Viruses................................................ 281 22.7.1 Respiratory Syncytial Virus...................................... 281 22.7.2 Parainfluenza Viruses................................................ 282 22.7.3 Influenza Viruses...................................................... 282 22.7.4 Adenoviruses............................................................ 282 References............................................................................ 283

O. Schildgen Kliniken der Stadt Köln gGmbH, Institut für Pathologie, Ostmerheimer Str. 200, 51109 Köln/Cologne, Germany and Private University, Witten/Herdecke, Germany e-mail: [email protected], [email protected]

22.1 Introduction Emerging infectious diseases according to the CDChosted journal Emerging Infectious Diseases (www. cdc.gov/ncidod/EID/about/background.htm) are defined as diseases “whose incidence in humans has increased in the past two decades or that are expected to have an increased incidence in the near future.” These diseases respect no regional, national, or international boarders and include (1) new infections resulting from changes or evolution of existing organisms, (2) known infections spreading to new geographic areas or populations, (3) previously unrecognized infections appearing in areas undergoing ecologic transformation, (4) old infections re-emerging as a result of antimicrobial resistance, and, finally and most importantly for the field of virology, (5) infections caused by newly discovered agents. After the discovery of the human metapneumovirus (hMPV) in 2001 and the 2002/2003 outbreak of severe acute respiratory syndrome (SARS), the number of known emerging viruses expanded at a fast pace, mainly due to the development of novel virus identification methods and their routine use in patients with suspected infections but negative findings from conventional diagnostic methods. This chapter focuses on these new pathogens and highlights their role in patients with hematological malignancies.

22.2 Human Metapneumovirus In 2001 the hMPV was described as the third known Paramyxovirinae to cause disease in humans, toget­ her with the respiratory syncytial virus (RSV) and

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_22, © Springer-Verlag Berlin Heidelberg 2011

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parainfluenza viruses (PIVs), all of which cause respiratory infections [204]. Infections with hMPV and RSV occur worldwide and are associated with a broad clinical spectrum ranging from mild to lifethreatening disease. Our group and others have shown that hMPV infections in hospitalized patients or in the elderly are at least as severe as RSV infections [125, 146, 147, 175, 178, 204–206, 218, 220, 221, 229]. Whether hMPV infections cause milder symptoms than RSV infections in otherwise healthy individuals has not yet been systematically investigated. Furthermore, hMPV and RSV often occur as copathogens and may then cross-react directly or indirectly [229]. Genetically, hMPV is most closely related to the avian metapneumovirus (APV) [204] and is assumed to have a zoonotic origin, a possibility supported by the fact that it can be transferred to APV-susceptible poultry. Serological and bioinformatic analyses indicate that passage to humans occurred more than 50 years ago [47, 48, 210]. In contrast to RSV, hMPV lacks two genes coding for the nonstructural proteins NS1 and NS2, both of which are assumed to interact with the host’s immune response. For this reason, RSV and hMPV may induce different host immune responses [25, 59, 122, 123, 144, 148, 191]. While RSV may be defined as a reemerging pathogen, at least in some patient cohorts where it was previously underestimated [174], hMPV has been shown to cause a number of severe respiratory events in patients with hematological malignancies. RSV infection and hMPV infection are indistinguishable on clinical grounds alone [229]. In one study including 114 lung transplant recipients, hMPV was detected in bronchoalveolar lavage (BAL) fluid from about 5% of symptomatic patients [45]. Further cases were described after lung and heart–lung transplantation in patients having histological findings of acute pneumonia with diffuse alveolar damage and hyaline membrane formation [112, 192]. In hematopoietic stem-cell transplant recipients, hMPV can cause life-threatening disease. Englund and colleagues described a case series in which the hMPV detection rate by RT-PCR was about 26% among symptomatic patients, and 80% of hMPV-positive patients died from severe infection [63]. Furthermore, in stem-cell transplant recipients, viral shedding and persistence may be prolonged compared to otherwise healthy individuals and may be accompanied by severe

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infection characterized by rapidly progressive pneumonia with diffuse alveolar hemorrhage [50, 63]. Until now, ribavirin has been the only antiviral agent used to treat severe hMPV infections [28, 85, 93, 165]. Ribavirin was tested in a mouse model and used successfully in two published clinical cases. To date, no other antivirals or vaccines are available.

22.3 Human Bocavirus Human bocavirus (HBoV) may be an emerging res­ piratory virus. It was first discovered in 2005 by the Swedish research group led by Tobias Allander at the Karolinska University Hospital in Stockholm [9]. The discovery was made possible by a novel molecular virus screening technique involving DNase treatment, random amplification, cloning, and sequencing. The newly found virus showed up as a possible cause of respiratory disease, particularly acute respiratory tract infections. Clinical symptoms include coughing, fever, and rhinorrhea. It is still unclear whether HBoV is able to trigger disease on its own or occurs only as a copathogen [176]. Comparisons of the genomic sequence to other known viruses suggest that HBoV may belong to the Parvoviridae family, Parvovirinae subfamily, and Bocavirus genus. This genus has two other viruses, namely, bovine parvovirus (BPV) and canine minute virus (CnMV). HBoV may be the second Parvoviridae known to cause human disease, after parvovirus B19, which belongs to the Erythrovirus genus. Several nonpathogenic parvoviruses are also known to infect humans, including the adeno-associated viruses (AAV) of the parvovirus family, Dependovirus genus, and, in the same family, parvovirus 4 (PARV4), a possible member of the Hokovirus genus [113]. Two new viruses classified as HBoV2 and HBoV3 were discovered recently. HBoV2 has 75% similarity to HBoV, compared to only 18% for HBoV3 and HBoV2 [12, 100]. HBoV2 was detected in children with acute gastroenteritis in England, Pakistan, and Australia, whereas HBoV3 was detected during the course of an HBoV2 surveillance program but could not be associated to any symptoms [12]. HBoV is a non-enveloped single-stranded DNA virus, encapsulated in a simple icosahedral shell with a diameter of 20–26 nm, made up by the arrangement of

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two proteins. The main genome body containing the open reading frames (ORFs) encoding viral proteins has been sequenced and shown to be 5,309 nt in length [115]. The entire genome length is predicted to be about 6,000 nt [8, 9]. Experiments to directly sequence the virus genome failed and led to faulty data [9, 27]. HBoV is thought to have palindromic hairpin structures flanking the terminal ends, similar to related Parvoviridae (e.g., BPV and CnMV). The function of the terminal folds is not fully understood, but it is thought that they act as primers in viral replication and are important for packaging [101]. Until now, it was not possible to decipher the unknown sequences. Attempts to amplify the regions encoding specific enzymes did not reveal the nucleotide sequence [9]. An undetected protein covalent or other protein modification on the HBoV genome may explain this failure, as other parvoviruses (B19, MVM, and H1) possess protein covalents attached to their genomes [39, 51, 168]. Recent findings reveal that the majority (87.5%) of the ssDNA strands packed in the capsid are of negative polarity, independent from their viral subtypes [27]. The genomic composition is as yet unconfirmed, and so far three ORFs have been identified, similar to BPV and CnMV. One of these ORFs encodes for the viral capsid proteins VP1 and VP2, whereas the other two encode for non-structural proteins. The VP2 gene sequence is nested within the VP1 gene sequence. The VP1 sequence, compared to VP2, contains a unique terminal sequence, VP1u [163], which may be required for HBoV genome transfer to the nucleus for replication [236]. The HBoV capsid is composed of 60 proteins, derived from the structural molecule VP1 and its derivative VP2 [9]. The functions of the non-structural proteins NS1 and NP-1 are still equivocal. NS1 may play a role in replication. It generally acts as an initiator protein (for parvoviruses), specifically controlling the process by which several concatemeric intermediates are processed by rolling-hairpin replication [15]. The role for NP-1, located in the middle ORF, is still unclear, but probably also involves parvovirus replication. The transmission route of HBoV is still unknown, but suggested tissue sites for replication are the respiratory and intestinal epithelia, as well as the lymphatic organs. Parvoviruses replicate only in proliferating cells, and the viral proteins are transcribed only during the S-phase. Recently, an in  vitro replication system for HBoV using stratified human airway epithelium to imitate the human trachea was successfully established.

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The cells were inoculated with HBoV-positive material from respiratory tract secretions of hospitalized children. Apical HBoV release from the cells was confirmed using PCR. This study further showed that the transcription model resembled that of both of the other known bocaviruses (BPV and MVC) [52]. Symptoms associated with possible HBoV infection are wheezing, fever, bronchiolitis, and pneumonia [8, 12, 19, 31, 33, 41, 43, 44, 49, 97, 114, 118–121, 124, 126, 141, 176, 177, 179, 183, 195, 198, 203, 213, 219, 226, 235, 237, 239]. However, the presence of HBoV in the respiratory tract does not prove that the virus is the cause of infection. HBoV is often detected concomitantly with other respiratory viruses [41, 216, 226], a fact that adds to the uncertainty regarding the pathogenic potential for HBoV [41, 66, 91, 97, 118, 124, 128, 136, 176, 200, 203, 213, 217, 226, 239]. The symptoms are identical in patients positive for HBoV alone or combined with another virus, but the viral load is higher in mono-infections than in coinfections. Asymptomatic patients can carry the virus. In one study, 43% of tested asymptomatic children were HBoV-positive. These patients were admitted for elective surgery, and the group undergoing mainly ear, nose, and throat surgery had the highest prevalence of asymptomatic HBoV infection [124]. These data suggested that HBoV may persist in the host in the tonsillar lymphoid tissue, contributing to tonsillar hyperplasia [126]. HBoV has been detected in patients with symptoms of gastrointestinal infection, but it is unclear whether the virus is only excreted in stool or is a cause of gastroenteritis. In these studies, HBoV was found concomitantly with a norovirus or other enteric viruses, and HBoV was not directly proven to be a cause of gastrointestinal infection. The virus in suspension in respiratory secretions may be simply swallowed and excreted in stool. The newly discovered HBoV2 and HBoV3 have both been detected in stool samples. HBoV2 was identified in a study involving stool sample screening in children with non-polio acute flaccid paralysis [12, 100, 179], and HBoV2 and HBoV3 were detected in hospitalized children with acute gastroenteritis. More studies on the two new HBoV types are needed to gain a better understanding of their role in gastrointestinal infections. No evidence that HBoV2 and HBoV3 can infect gastrointestinal tissue exists to date. Furthermore, whether detection of these viruses in serum indicates viremia or infection of blood cells is unknown, because there are no currently established methods for detecting HBoV particles. The related parvovirus B19

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can infect erythroid progenitor cells in the bone marrow, but no HBoV DNA was detected in bone marrow samples from human immunodeficiency virus (HIV)positive and -negative individuals, whereas B19 was present in both groups [76, 146]. So far, there is one published report of HBoV associated with severe pneumonia in a pediatric hematopoietic stem cell transplant recipient [172, 173] and one of HBoV infection in an adult with leukemia [109]. However, none of these patients had clinical symptoms different from those caused by other “common cold” pathogens, and no specific antiviral therapy was available. Since the discovery of HBoV, infections with this virus have been found worldwide. The prevalence of infections in which HBoV may be a causative factor ranges from 1.5% to 19.3%. No seasonal variations have been described. HoBV occurs mainly in pediatric patients aged 6–24 months [4, 5, 9, 10, 12, 16, 17, 37, 40, 42, 44, 61, 74, 77, 86, 91, 95, 99, 103, 116, 127, 132, 143, 149, 158, 160, 162, 166, 167, 179, 187, 189, 194, 214, 219, 226, 235, 238]. Younger children may be protected by maternal antibodies [38]. HBoV-IgG can cross the placental barrier, but it is unclear whether HBoV can be transmitted from the mother to her fetus. Antibodies against HBoV have been found in about 94% of individuals older than 19 years of age [44]. At the moment, only two different genotypes of the single HBoV lineage are known. A simple verification test is available for rapidly differentiating between these two genotypes. Digestion of a 309-bp fragment of the VP1/VP2 gene with BstAPI endonuclease yields two fragments with genotype 1, but induces no cleavage with genotype 2 [54]. Three HBoV2 genotypes have been identified [5], but no information is available for HBoV3. Despite a large number of clinical studies, the biological background of HBoV is still unknown. The virus can be replicated in a cell line. However, complete genome sequencing is needed to fully understand the virus. As this virus may cause acute respiratory disease, it is crucial to understand the disease process and its causative agent.

22.4 Human Coronaviruses As of August 2009, five human coronaviruses (CoVs) were known, of which three meet the definition of emerging pathogens. The five human CoVs are OC43

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and 229E, two long-known viruses that cause respiratory and/or gastrointestinal disease, and the emerging viruses SARS-CoV [56], NL63 [207], and HKU-1 [233]. SARS-CoV appears to be an archetypical zoonosis responsible for a single outbreak, which was unfortunately accompanied with high mortality and had the potential for a pandemic event. The two other newly detected CoVs, NL63 and HKU-1, occur periodically and infect all age groups worldwide. After the identification in the 1960s of the first CoVs known to cause human disease, HCoV-229E and HCoV-OC43, and their association with mild respiratory disease [30, 34, 67, 84, 137, 142], little new information emerged in this field until the beginning of the twenty-first century. In 2002/2003, a CoV appeared in the Guangdong province of China, causing severe acute respiratory syndrome (SARS) [56, 108, 156]. SARS was fatal in some patients, although at the time CoVs were believed to cause only mild disease. Strenuous efforts were made to identify and to characterize this new virus and to curb its potential for causing a pandemic. Among the heterogeneous Coronaviridae family, CoV NL63 (HCoV-NL63) was identified in 2004 [207] and CoV HKU1 (HCoV-HKU1) in 2005 [232]. In contrast to SARS-CoV, these newly detected CoV led to clinical symptoms similar to those caused by HCoV-229E and HCoV-OC43. Considerable research has been undertaken to learn more about these viruses, their differences, similarities, and characteristics. This review focuses mainly on SARS-CoV and HCoV-NL63. Several techniques were employed to characterize and to identify the agent causing SARS. Tests for known respiratory viruses were negative. Patient samples were inoculated onto Rhesus monkey kidney cells (fRhk4) to look for cytopathic effects. Electron microscopy revealed the morphology of the virus and led to characterization of the virus family. Histopathological studies showed mild interstitial inflammation with scattered alveolar pneumocytes. In an immunofluorescence antibody assay, sera from patients had high titers of antibodies against the infected cells. A random RT-PCR assay generated DNA fragments of unknown origin, but with homology to viruses of the Coronaviridae family, and confirmed the results of electron microscopy. A few days later, these results were confirmed by two other groups [56, 108, 156].

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SARS and its causative agent appeared unexpectedly and spread explosively. The infection was transmitted from palm civets to humans, although it has since been confirmed that bats are the natural reservoir of SARSCoV. Due to the fast mutation rate of RNA viruses and their resulting genotypic markers, the course of the infection could be reconstituted in great detail. In the early phase of the SARS near pandemic, the very first index patient fulfilling the subsequent WHO definition of SARS resided in Foshan near Guangzhou and was identified on November 16, 2002. One month later, the second case occurred, in Shenzhen, where a man who had regular contact with wild animals was infected and transmitted the disease to his family and to several staff members at the hospital where he was admitted. Similar cases were reported nearby. In January 2003, the second phase of the SARS outbreak started in Guangzhou. Several patients died, and patients were transferred to major hospitals, leading to nosocomial spread of the virus to other patients and health-care workers. The next and final phase started in mid-February 2003 and heralded the pandemic. A doctor was infected in Guangdong province and took the disease to Hong Kong, where he stayed in a hotel (“hotel M”). He infected 17 other people, who were admitted to different hospitals, where further nosocomial infections occurred. Some of the infected patients transferred the virus via air travel to Vietnam, Singapore, and Toronto, where new cases emerged. A novel CoV was identified on March 21, 2003, and confirmed a few days later. The first strain (Tor2) was fully sequenced on April 12, 2003, and SARS-CoV was proven to be the cause of SARS [134]. In July 2003, the epidemic ended, with no further human-to-human transmissions being reported. In September 2003, a new case was reported at a laboratory in Singapore, and over the next 2 years other accidents occurred in laboratories. HCoV-NL63 was discovered in a 7-month-old child with bronchiolitis. Diagnostic tests for all known respiratory viruses were negative. Inoculation of a sample on tMK and, later on, LLC-MK2 cell cultures produced a cytopathic effect. In the LLC-MK2 cell culture supernatant, a new virus was identified using the VIDISCA method [161, 207]. Sequence comparisons established that the virus was most closely related to HCoV-229E and, together with PEDV and Bat-CoV, belonged to the coronavirus subgroup 1b. Two further research groups obtained identical results soon afterward [65, 72].

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There is some indication in the literature that HCoV-NL63 was detected much earlier. Viruses were described that did not exhibit all the characteristics of HCoV-229E or HCoV-OC43. Unfortunately, these isolates were lost, so that studies could not be done to determine whether one or more of them were identical to HCoV-NL63. SARS-CoV and HCoV-NL63 are both members of the Coronavirus genus, Coronaviridae family, within the Nidovirales order. Both organisms are positive single-stranded RNA viruses with a large genome of about 30 kb. The virus particles are enveloped and possess peculiar spike-shaped proteins on their surface that produce a crown-like appearance. Electron microscopy revealed particles of 80–140 nm located either within the infected cells at the rough endoplasmic reticulum in double-membraned vesicles or outside the cells attached to the plasma membrane. The genomes of both SARS-CoV and HCoV-NL63 can be roughly divided into two parts. The 5¢ twothirds consists of one large polyprotein (ORF1ab) including several domains with autocatalytic activities, producing nonstructural proteins (NSPs) involved in replication and immune evasion. ORF1ab encodes 16 NSPs in toto in both SARS-CoV and HCoV-NL63. The last third at the 3¢ end of the genome contains the ORFs coding for the functional proteins – spike (S), envelope (E), membrane (M), and nucleocapsid (N) – and for accessory protein genes that vary in number and position across species. Traditionally, CoVs were classified – due to their antigenic cross-reactivity – into three groups, which were largely confirmed later on by sequence analysis results. Group I and II viruses infect mammals, whereas group III viruses infect only birds. While HCoV-NL63 belongs to group 1b, SARS-CoV and the bat CoVs are considered group 2b viruses, although bat CoVs constitute a newly identified CoV group. HCoV-NL63 is most closely related to HCoV-229E, and phylogenetic analysis findings suggest that HCoV-NL63 may have diverged from HCoV229E in the twenty-first century. Furthermore, there seem to be two main genetic clusters of HCoV-NL63, and there is evidence that the HCoV-NL63 genome is arranged in a mosaic-like manner. Patients infected with HCoV-NL63 usually experience only mild symptoms, including cough, rhinitis, rhinorrhea, and pharyngitis, often with a fever. In rare cases, pneumonia can occur, chiefly in children aged 0–3 years, older people, and immunocompromised

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individuals. Among children with severe lower respiratory tract infection, a substantial number have croup compared to a control group. Croup or laryngotracheobronchitis is characterized by a loud barking cough, inspiratory stridor, and hoarseness. An association with Kawasaki disease has been postulated but not confirmed despite studies by a number of research groups [11, 14, 15, 53, 58, 87, 106, 111, 140, 188, 190, 193, 202, 208]. After the detection of HCoV-NL63 in The Netherlands and, later on, in New Haven, CT, USA, this virus was found in a number of countries, suggesting a worldwide distribution. Except in subtropical regions, HCoV-NL63 was mainly detected in the winter months and often turned up with other co-pathogens, such as influenza, RSV, parainfluenza, and hMPV. The HCoV-NL63 load is attenuated when there is another pathogen. However, and not surprisingly, the infection itself seems more severe in co-infections. As with SARS-CoV, HCoV-NL63 is detectable up to 2 months after recovery from the disease. Seroprevalence studies showed that virtually every adult encounters HCoV-NL63 at least once in a lifetime. Antibodies specific for the S protein are produced and display a neutralizing effect. People infected with SARS-CoV had a fever, chills, myalgia, rigor, and a nonproductive cough. Clinical symptoms such as rhinorrhea and sore throat were less common. In contrast to HCoV-NL63, SARS-CoV did not infect children, and the disease occurred instead in normal and healthy adults and in the elderly. Of 8,096 infected people, 774 died, demonstrating a nearly 10% mortality rate. SARS-CoV spread to more than 30 countries [26, 29, 35, 94, 186, 227]. The first outbreak occurred in late 2002/early 2003. Seasonality of HCoV-NL63 infection is not known, as the pandemic occurred only once, with the peak in winter. It has been confirmed that SARS-CoV is a zoonosis that originates primarily from bats. Although SARS-CoV was initially spread from civets to humans, the actual transmission route was from humans to humans, most likely by droplets, and probably occurred in health-care facilities, at workplaces, and when using public transportation. The virus was detected not only in the respiratory tract, but also in the gastrointestinal tract, liver, kidney, brain, and other tissues. Seroprevalence was quite low among the general population, ranging across studies from 0% to 1.81% and being slightly higher in asymptomatic health-care

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workers. In contrast, a much higher rate (up to 40%) was found in asymptomatic animal handlers, which was not surprising, as these individuals probably acquired immunity via less pathogenic SARS-CoVlike strains that also emerged by zoonotic recombinations. SARS-CoV infection can be accompanied by co-pathogens such as other respiratory viruses (e.g., hMPV) or other CoVs. The association of SARS-CoV with severe pneumonia in patients with hematological malignancies occurred only during the single outbreak, and studies on the role for NL63 in these high-risk patients are still limited. However, 229E has been detected in hematopoietic stem cell transplant recipients with high fever, cough, and interstitial and alveolar lung disease [157].

22.5 Polyomaviruses Recently, two novel polyomaviruses were detected in respiratory aspirates. Allander et al. in Sweden discovered a previously unrecognized third human polyomavirus in 6 (1%) of 637 nasopharyngeal aspirates and 1 (0.5%) of 192 fecal samples, and suggested the name KI polyomavirus (KIPyV) [7]. The second newly identified polyomavirus was found by Gaynor et  al. in respiratory samples from Bribane, Australia, and St. Louis, MO, USA. This “Washington University” (WU) genome polyomavirus (WUPyV) was amplified and cloned from the nasopharyngeal aspirate of a 3-yearold patient with pneumonia and negative tests for other respiratory viruses. Screening of 2,135 patients with respiratory tract infections identified 43 additional cases [79]. Of note, KIPyV was not named for the Karolinska Institute in Stockholm where it was detected. Since the first description of KIPyV and WUPyV, a number of prevalence studies from various areas have been published, but the association of these viruses with acute respiratory tract infections remains unclear [2, 13, 117]. Prevalence studies of KIPyV and WUPyV showed a worldwide distribution. The prevalence of KIPyV was 1% in Sweden, 1.4% in the United Kingdom, 1.99% in Thailand, and 2.6% in Australia [7, 23, 152, 155]. The prevalence of WUPyV was higher, 7% in South Korea, and 6.29% in Thailand [88, 155]. Australia, the USA, and the UK had WUPyV prevalences of 4.5%, 1.2%,

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and 1.0%, respectively [23, 79, 152]. The age distribution of KIPyV- and WUPyV-infected patients showed two peaks, in patients younger than 15 years (with the highest rates occurring before 5 years of age) and older than 45 years [3, 150]. Seasonal variations in KIPyV and WUPyV did not appear consistently. KIPyV infections predominated during the winter months in Thailand but not in Australia. In contrast, WUPyV infections were predominantly detected during late winter, peaking in December to early summer in Australia but not in Thailand [23, 24, 155]. KIPyV and WUPyV are frequently associated with other respiratory viruses. High co-detection rates were found in Australia, 74.7% for KIPyV and 79.7% for WUPyV, and the most commonly co-detected viruses were human rhinovirus and HBoV. Co-detection of KIPyV and WUPyV was found in 14 patients, of whom only 1 had no other respiratory virus [23]. Norja et al. detected KIPyV or WUPyV in 19 patients and found a viral coinfection rate of nearly 50% with predominant detection of adenoviruses. The overall frequencies of KIPyV and WUPyV detection were similar in patients with upper respiratory tract infection, lower respiratory tract infection, or no respiratory symptoms, and eight patients were immunosuppressed, although overall the patient groups were not very well described [152]. Data are not available to determine whether KIPyV and WUPyV detection represents a similar phenomenon to JCV and BKV reactivation in immunocompromised patients, or whether KIPyV and WUPyV share the oncogenic potential of other human and animal polyomaviruses, and further studies are needed [242]. However, Koch’s modified postulates have not been verified so far, and whether KIPyV and WUPyV are respiratory pathogens or innocent bystanders is still debated. Further studies are required to evaluate the clinical relevance of KIPyV and WUPyV detection in respiratory specimens. Another newly recognized polyoma virus of interest may be the Merkel cell polyoma virus, MCPyV, recently identified in Merkel cell carcinoma. MCPyV may have oncogenic potential, as it is found mainly in lesional and non-lesional skin from patients with Merkel cell carcinoma and other skin diseases [73]. This oncogenic potential, as well as experience with other oncogenic viruses such as EBV, suggests a high likelihood of MCPyV generating clinical events in patients with hematological malignancies. However, until now, there are more questions than answers

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regarding this new virus. The role for MCPyV in disease is unclear, and cell-culture and animal models are not yet available [169].

22.6 Picornaviruses Within the group of picornaviruses, two emerging virus lines were identified recently, namely, rhinovirus X associated with severe respiratory disease and the parechoviruses. The newly identified rhinovirus [105, 129, 171] causes common colds that can progress to fatal infections in high-risk patients. The role for this virus in patients with hematological malignancies is unclear. The number of known parechoviruses is growing rapidly, as novel identification methods have led to the discovery of new variants. Parechoviruses were classified in the Enterovirus genus initially, then found to exhibit different biological features, leading to their reclassification in their own genus. Clinically, they cause the same spectrum of disease as enteroviruses. The rodent parechovirus known as Ljungan virus is believed to be associated with greater disease severity [1, 6, 20–22, 55, 68, 90, 96, 107, 151, 170, 199, 209, 212, 223, 230, 231, 234, 240, 241]. As with enteroviruses, parechoviruses deserve careful attention in highrisk patients.

22.7 Reemerging Viruses 22.7.1 Respiratory Syncytial Virus The RSV has been known for decades and is not believed to be an emerging pathogen. However, recent investigations have demonstrated clearly that RSV infection is underestimated in the elderly and in patients with other malignancies, where it may cause severe to fatal pneumonia [174, 182, 184, 185, 196, 197, 215, 222]. This increasing incidence in some patient groups may define the RSV as a reemerging pathogen, although it is ascribable to the use, for the first time, of molecular RSV diagnostic methods in vulnerable patient groups. In all likelihood, the RSV was present in these groups previously but went unrecognized.

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RSV accounts for a large number of infections throughout the treatment of patients with acute lymphoblastic leukemia. In one study, about 57% of patients were positive for RSV at some point in time [102]. RSV is also of clinical significance following allogeneic bone marrow transplantation and has been found in a substantial proportion of patients with lung infections [64, 133]. Furthermore, RSV was responsible for 55% of fatal pneumonia cases in adult immunocompromised patients treated for lymphoma and leukemia in a retrospective study and was a major cause of viral pneumonia in several cohorts of patients with these hematological malignancies [57, 78, 81, 82, 164, 201, 228]. In patients with hematological malignancies, and most notably in hematopoietic stem cell recipients, RSV infection is fatal in up to 80% of cases [89]. In these patients, ribavirin, immunoglobulins, and the RSV-specific humanized monoclonal antibody palivizumab may be used as specific therapy and/or prophylaxis [18, 32, 36, 38, 60, 69, 70, 75, 80, 83, 104, 110, 138, 139, 145, 159, 181, 211, 224, 225]. However, evidence supporting the use of these treatments remains weak at this time.

22.7.2 Parainfluenza Viruses Clinically, parainfluenza viruses 1–4 cannot be differentiated from RSV or hMPV infection. As they infect the same groups of patients and cause identical symptoms, they require the same attention as other pathogens. They can also be classified among reemerging viruses, as screening was recently introduced. Parainfluenza viruses should be considered in the differential diagnosis of respiratory infection and distinguished from emerging pathogens [98, 154].

22.7.3 Influenza Viruses Influenza viruses are not emerging viruses, as in theory all potential variants and reassortants are identified based on well-known data on the mode of replication and influenza-associated biological phenomena such as antigen shift. Nevertheless, perhaps due to concern that a lethal variant similar to the Spanish flu may

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return, or due to the awarding of research grants based on this fear, any “novel” influenza virus variant is estimated to have pandemic potential and is therefore classified as an emerging pathogen (and as an opportunity for the media to generate widespread fear of general social disorganization and massive mortality). The most recent virus classified as an emerging influenza virus was the Mexican H1N1 strain identified in 2009. Recent developments in the swine-originated H1N1 pandemic indicate that the main target is not the elderly population but, instead, younger adults (www.who.org [153, 180]). The immunosenescence concept suggested that older people would be at greatest risk. The predominant involvement of younger individuals suggests a role for unknown factors that contribute to clinical disease. Alternatively, aging might exert a protective effect. However, it must be hoped that the current wave of H1N1 influenza is not a relatively harmless prelude to a second severe outbreak later in the flu season. As with any influenza variant, the H1N1 strain warrants close attention in high-risk patients. All influenza variants can cause severe pneumonia in patients with hematological malignancies.

22.7.4 Adenoviruses Adenoviruses are small naked DNA viruses that occur worldwide and mainly infect children between 0.5 and 5 years of age. The clinical spectrum ranges from mild to severe respiratory diseases to epidemic keratoconjunctivitis (“pink eye”), tonsillopharyngitis, and gastroenteric disorders (vomiting, diarrhea). Adenoviruses occur in over 50 serotypes, affecting all age groups and causing diseases that are usually self-limiting within 14 days or asymptomatic [46, 62, 71, 92, 130, 131, 135]. Importantly, adenoviruses may persist in the infected host [46, 62, 71, 92, 130, 131, 135] and may undergo reactivation in immunosuppressed patients, including those with hematological malignancies. Adenoviruses play a major role in solid-organ transplant recipients but occur less often in stem cell recipients [46, 62, 71, 92, 130, 131, 135], However, novel and more aggressive adenovirus strains may meet the definition for emerging pathogens and may play a future role in patients with hematological

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malignancies. Consequently, adenoviruses deserve attention. More specifically, shedding may be prolonged in high-risk patients, patient isolation may be required, and no antiviral therapy for adenoviruses is available so far [46, 62, 71, 92, 130, 131, 135].

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290 human parechovirus in the Netherlands in 2000 to 2007. J Clin Microbiol 46:2884–2889 210. Velayudhan BT, Nagaraja KV, Thachil AJ, Shaw DP, Gray GC, Halvorson DA (2006) Human metapneumovirus in turkey poults. Emerg Infect Dis 12:1853–1859 211. Venkatesh MP, Weisman LE (2006) Prevention and treatment of respiratory syncytial virus infection in infants: an update. Expert Rev Vaccines 5:261–268 212. Verboon-Maciolek MA, Groenendaal F, Hahn CD, Hellmann J, van Loon AM, Boivin G, de Vries LS (2008) Human parechovirus causes encephalitis with white matter injury in neonates. Ann Neurol 64:266–273 213. Vicente D, Cilla G, Montes M, Perez-Yarza EG, PerezTrallero E (2007) Human bocavirus, a respiratory and enteric virus. Emerg Infect Dis 13:636–637 214. Villa L, Melon S, Suarez S, Alvarez-Arguelles ME, Gonzalez D, Morilla A, Boga JA, Rodriguez J, de Ona M (2008) Detection of human bocavirus in Asturias, Northern Spain. Eur J Clin Microbiol Infect Dis 27:237–239 215. Voigt E, Tillmann RL, Schewe JC, Molitor E, Schildgen O (2008) ARDS in an HIV-positive patient associated to respiratory syncytial virus. Eur J Med Res 13:131–132 216. Volz S, Schildgen O, Klinkenberg D, Ditt V, Muller A, Tillmann RL, Kupfer B, Bode U, Lentze MJ, Simon A (2007) Prospective study of Human Bocavirus (HBoV) infection in a pediatric university hospital in Germany 2005/2006. J Clin Virol 40:229–235 217. Volz S, Schildgen O, Muller A, Tillmann RL, Eis-Hubinger AM, Kupfer B, Bode U, Lentze ML, Simon A (2007) The human bocavirus: pathogen in airway infections? Dtsch Med Wochenschr 132:1529–1533 218. von Linstow ML, Eugen-Olsen J, Koch A, Winther TN, Westh H, Hogh B (2006) Excretion patterns of human metapneumovirus and respiratory syncytial virus among young children. Eur J Med Res 11:329–335 219. von Linstow ML, Hogh M, Hogh B (2008) Clinical and epidemiologic characteristics of human bocavirus in Danish infants: results from a prospective birth cohort study. Pediatr Infect Dis J 27:897–902 220. von Linstow ML, Hogh M, Nordbo SA, Eugen-Olsen J, Koch A, Hogh B (2008) A community study of clinical traits and risk factors for human metapneumovirus and respiratory syncytial virus infection during the first year of life. Eur J Pediatr 167:1125–1133 221. von Linstow ML, Larsen HH, Eugen-Olsen J, Koch A, Nordmann Winther T, Meyer AM, Westh H, Lundgren B, Melbye M, Hogh B (2004) Human metapneumovirus and respiratory syncytial virus in hospitalized danish children with acute respiratory tract infection. Scand J Infect Dis 36:578–584 222. von Renesse A, Schildgen O, Klinkenberg D, Muller A, von Moers A, Simon A (2009) Respiratory syncytial virus infection in children admitted to hospital but ventilated mechanically for other reasons. J Med Virol 81:160–166 223. Wakatsuki K, Kawamoto D, Hiwaki H, Watanabe K, Yoshida H (2008) Identification and characterization of two strains of human parechovirus 4 isolated from two clinical cases in Fukuoka City, Japan. J Clin Microbiol 46:3144–3146 224. Wang D, Cummins C, Bayliss S, Sandercock J, Burls A (2008) Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: a systematic

O. Schildgen review and economic evaluation. Health Technol Assess 12:iii, ix–x, 1–86 225. Weisman LE (2009) Respiratory syncytial virus (RSV) prevention and treatment: past, present, and future. Cardiovasc Hematol Agents Med Chem 7:223–233 226. Weissbrich B, Neske F, Schubert J, Tollmann F, Blath K, Blessing K, Kreth HW (2006) Frequent detection of bocavirus DNA in German children with respiratory tract infections. BMC Infect Dis 6:109 227. Wenzel RP, Bearman G, Edmond MB (2005) Lessons from severe acute respiratory syndrome (SARS): implications for infection control. Arch Med Res 36:610–616 228. Whimbey E, Couch RB, Englund JA, Andreeff M, Goodrich JM, Raad V II, Lewis NM, Luna MA, Baxter B et al (1995) Respiratory syncytial virus pneumonia in hospitalized adult patients with leukemia. Clin Infect Dis 21:376–9 229. Wilkesmann A, Schildgen O, Eis-Hubinger AM, Geikowski T, Glatzel T, Lentze MJ, Bode U, Simon A (2006) Human metapneumovirus infections cause similar symptoms and clinical severity as respiratory syncytial virus infections. Eur J Pediatr 165:467–475 230. Williams CH, Panayiotou M, Girling GD, Peard CI, Oikarinen S, Hyoty H, Stanway G (2009) Evolution and conservation in human parechovirus genomes. J Gen Virol 90:1702–1712 231. Wolthers KC, Benschop KS, Schinkel J, Molenkamp R, Bergevoet RM, Spijkerman IJ, Kraakman HC, Pajkrt D (2008) Human parechoviruses as an important viral cause of sepsislike illness and meningitis in young children. Clin Infect Dis 47:358–363 232. Woo PC, Lau SK, Chu CM, Chan KH, Tsoi HW, Huang Y, Wong BH, Poon RW, Cai JJ, Luk WK, Poon LL, Wong SS, Guan Y, Peiris JS, Yuen KY (2005) Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia. J Virol 79:884–895 233. Woo PC, Lau SK, Huang Y, Tsoi HW, Chan KH, Yuen KY (2005) Phylogenetic and recombination analysis of coronavirus HKU1, a novel coronavirus from patients with pneumonia. Arch Virol 150:2299–2311 234. Yamamoto M, Abe K, Kuniyori K, Kunii E, Ito F, Kasama Y, Yoshioka Y, Noda M (2009) Epidemic of human parechovirus type 3 in hiroshima city, Japan in 2008. Jpn J Infect Dis 62:244–245 235. Yu JM, Li DD, Xu ZQ, Cheng WX, Zhang Q, Li HY, Cui SX, Miao J, Yang SH, Fang ZY, Duan ZJ (2008) Human bocavirus infection in children hospitalized with acute gastroenteritis in China. J Clin Virol 42:280–285 236. Zadori ZSJ, Lacoste MC, Li Y, Gariepy S, Raymond P, Allaire M, Nabi IR, Tijssen P (2001) A viral phospholipase A2 is required for parvovirus infectivity. Cell Dev 1: 291–302 237. Zhang LL, Tang LY, Xie ZD, Tan XJ, Li CS, Cui AL, Ji YX, Xu ST, Mao NY, Xu WB, Shen KL (2008) Human bocavirus in children suffering from acute lower respiratory tract infection in Beijing Children’s Hospital. Chin Med J (Engl) 121:1607–1610 238. Zhao LQ, Qian Y, Zhu RN, Deng J, Wang F, Dong HJ, Sun Y, Li Y (2009) Human bocavirus infections are common in Beijing population indicated by sero-antibody prevalence analysis. Chin Med J (Engl) 122:1289–1292

22  Emerging Viral Infections 239. Ziegler S, Tillmann RL, Muller A, Simon A, Schildgen V, Schildgen O (2008) No gastroenteric Bocavirus in high risk patients stool samples. J Clin Virol 43:349–350 240. Zoll J, Erkens Hulshof S, Lanke K, Verduyn Lunel F, Melchers WJ, Schoondermark-van de Ven E, Roivainen M, Galama JM, van Kuppeveld FJ (2009) Saffold virus, a human Theiler’s-like cardiovirus, is ubiquitous and causes infection early in life. PLoS Pathog 5:e1000416

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Cytomegalovirus Pneumonia in Patients with Hematologic Malignancies

23

Karen J. Vigil and Roy F. Chemaly

Contents 23.1 Introduction............................................................. 293 23.2 Cytomegalovirus Pneumonia................................. 294 23.2.1 Epidemiologic Characteristics.................................. 294 23.2.2 Clinical Presentation................................................. 294 23.2.3 Diagnosis.................................................................. 294 23.2.4 Treatment.................................................................. 296 23.2.5 Outcome.................................................................... 297 23.3 Prevention................................................................ 298 References............................................................................ 298

K.J. Vigil (*) Division of Infectious Diseases, The University of Texas Health Science Center at Houston Medical School, 6431 Fannin, MSB 6.119, Houston, TX 77030, USA e-mail: [email protected] R.F. Chemaly Department of Infectious Diseases, Infection Control, and Employee Health, Unit 402, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA e-mail: [email protected]

23.1 Introduction Cytomegalovirus (CMV) is a ubiquitous virus that is found in all geographic locations and infects people from all socioeconomic groups. In the United States, approximately 60% of individuals 6 years of age or older have been infected with CMV; worldwide, the incidence ranges from 60% to 100% [28]. CMV, a DNA virus belonging to the Herpesviridae family, infects more humans than does any other virus. As with other herpesviruses (i.e., Epstein-Barr virus; herpes simplex viruses 1 and 2; varicella-zoster virus; and human herpesviruses 6, 7, and 8), CMV remains latent in the host and has the potential to be reactivated, causing disease. Transmission of CMV occurs from person to person through bodily fluids. Primary CMV disease can cause severe infection when acquired congenitally; however, when acquired postnatally, it usually manifests as a benign mononucleosis-like syndrome. CMV disease is a frequent complication in patients with hematologic malignancies and may cause significant morbidity and mortality. CMV disease can be caused by reactivation of an endogenous virus or by infection from a transplanted organ or, rarely, a blood product transfusion. CMV infection in immunocompromised patient enhances immune suppression, favoring the development of other opportunistic infections and increasing the incidence of graft failure [5, 24, 29]. The lack of a preserved immune system combined with increased viral activation commonly produces severe systemic disease in these patients, who may develop viremia, pneumonia, gastrointestinal disease, hepatitis, meningoencephalitis, polyradiculopathy, and/or retinitis.

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_23, © Springer-Verlag Berlin Heidelberg 2011

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23.2 Cytomegalovirus Pneumonia 23.2.1  Epidemiologic Characteristics CMV pneumonia is uncommon in immunocompetent patients. However, immunosuppressed patients are at higher risk of developing CMV pneumonia, which is associated with a high mortality rate even when treated with aggressive antiviral therapy. A recent study reported an incidence of CMV pneumonia in immunocompromised patients of 3%; of the patients studied, 68% were hematopoietic stem cell transplant (HSCT) recipients, 20% had lymphoma, and 12% had leukemia [25]. In HSCT recipients, CMV pneumonia was one of the most common life-threatening infectious complications with an incidence of 10–30% in allogeneic HSCT recipients compared to 2% in autologous HSCT recipients, who usually develop a less severe form of the disease [31]. The use of preemptive therapy has significantly reduced the incidence rate [12]. However, the development of late CMV disease (>100 days posttransplant) is occurring more frequently and is associated with a high relapse rate and poor outcome [2]. In patients with leukemia, the reported incidence of CMV pneumonia is 2.9% [25]. In patients with lymphoma, CMV pneumonia has an overall incidence of 1.1%, and its incidence is increasing [5]. CMV pneumonia is the most common presentation of CMV disease (82%) and is more common in non-Hodgkin’s lymphoma patients (89%) than in other immunocompromised patients [30]. The mean time to onset of CMV pneumonia after HSCT transplant is 45 days (range, 2 weeks to > 2 years) [9]. However, with the use of prophylaxis, time of onset has been delayed to a median of 169 days (range, 96–184 days) [2]. In HSCT recipients, risk factors for developing CMV pneumonia include old age, graft-versus-host disease, positive serology of the HSCT donor, use of granulocyte transfusions from seropositive donors, total body irradiation, depleted antithymocyte globulins, receipt of T-cell-depleted stem cells, and circulating CMV DNA [15, 22]. On the other hand, the use of leukocyte-depleted platelets and CMV-seronegative red blood cells reduce the risk of CMV pneumonitis [3]. In patients with leukemia, use of lymphocytotoxic chemotherapeutic agents has been associated with the development of CMV pneumonia [25]. In patients with lymphoma, more cases occur in patients with B-cell

K.J. Vigil and R.F. Chemaly

non-Hodgkin’s lymphoma (89%), active disease (86%), advanced-stage disease (stage III/IV) (92%), or recurrent disease (55%) [5].

23.2.2 Clinical Presentation The clinical manifestations of CMV pneumonia in patients with hematologic malignancies are nonspecific. The most common presenting signs and symptoms are fever (80–90%), dry cough (65%), and dyspnea (55%). The disease is severe, and patients frequently require admission to the intensive care unit [5]. Hypoxemia is common and is a poor prognostic sign; patients can progress rapidly to respiratory failure requiring mechanical ventilation, especially if untreated. Severe lymphopenia (<200 lymphocytes/ mL) is common and significantly associates with a high mortality [25]. Although not clinical evident, an autopsy-based study demonstrated that 48% of cases had disseminated infection (adrenitis, nephritis, and colitis most commonly). In HSCT patients, symptomatic disease was described to occur most commonly post engraftment and before day 30 after transplant, when mucosal damage is maximal from chemotherapy. However, with the introduction of ganciclovir prophylaxis and preemptive treatment, CMV disease has been observed more frequently later after transplantation, with a median onset of day 160 [1, 2, 12]. CMV infection can predispose the host to other concomitant infections from opportunistic microbes (i.e., bacterial, fungal, or viral) [5, 29]. In these cases, the role of CMV should not be underestimated.

23.2.3 Diagnosis Diagnosis is difficult and challenging. An autopsybased study found that of CMV pneumonia patients with a postmortem diagnosis, only 64% had an antemortem diagnosis, and only 60% of patients with an antemortem diagnosis had received treatment. [29] The diagnosis of CMV pneumonia requires both clinical and radiographic evidence of pneumonia (Figs.  23.1–23.3) as well as isolation of CMV in bronchoalveolar lavage (BAL) fluid or lung-tissue specimens by culture, cytology, immunohistochemical

23  Cytomegalovirus Pneumonia in Patients with Hematologic Malignancies

Fig.  23.1  Computerized tomography scan of a 75-year-old patient with chronic lymphocytic leukemia and CMV pneumonia showing areas of ground-glass appearance and interstitial opacities in both lower lobes (left more than right)

Fig.  23.2  Chest X-ray of a patient with chronic lymphocytic leukemia and CMV pneumonia showing interstitial opacities in both bases

staining, histopathologic examination, or in situ hybridization [20].

23.2.3.1  Radiologic Findings The radiologic appearances of CMV pneumonia varied widely, with no pattern sufficiently characteristic to

295

Fig.  23.3  Patients with hematologic malignancies and CMV pneumonia frequently develop superimposed infections. Chest X-ray of a 72-year-old patient with chronic lymphocytic leukemia developed CMV and Stenotrophomonas maltophilia pneumonia showing diffuse consolidation in both lungs

allow differentiation of CMV pneumonia from other causes of pneumonia. The most common presentations are bilateral asymmetric ground-glass opacities, airspace opacities, and small centrilobular nodules [16]. However, atypical patterns are not uncommon, and normal chest X-rays have been reported, making it an entity difficult to diagnose on the bases of only ­imaging [10]. Histopathologically, areas of ground-glass attenuation and/or consolidation on CT scans correspond to the areas of alveolar damage that contain cytomegalic cells, hemorrhage, neutrophilic exudates, fibrinous exudates, and hyaline membranes; the lymphocytic interstitial infiltrates that cause alveolar wall or interlobular septal thickening also are seen as ground-glass attenuation. Nodules correspond to inflammatory or hemorrhagic areas or organizing pneumonia, while the centrilobular nodules represent the areas of intralveolar collections of macrophages, red blood cells, and fibrin [18].

23.2.3.2 Lung Biopsy/Cytology A definitive diagnosis of CMV pneumonia should be based on detection of the virus in lung tissue specimens by immunohistochemical staining, histopathologic evaluation for viral inclusions, or culture (Fig.  23.4). However, lung biopsies are rarely performed in immunocompromised patients because of

296

Fig. 23.4  CMV pneumonia. Early owl eye showing nuclear condensation, perinuclear clearing, and typical eosinophilic granules in the cytoplasm (Contribution of Jeffrey J. Tarrand, M.D.)

increased complications, inconsistent diagnosis, and questionable reliability. Therefore, bronchoalveolar lavage becomes a safe, effective, and rapid method for diagnosing CMV pneumonia in immunocompromised patients. In HSCT recipients, identification of CMV by a rapid centrifugation viral culture of BAL fluid has been shown to be highly correlated with CMV detection in lung tissue specimens [8].

23.2.3.3  Microbiology Viral cultures are the gold standard for diagnosing CMV infection. However, they have a poor predictive value, lack of quantitation, false-negative results, and long turnaround time (1–6 weeks). Shell vial centrifugation cultures are a modification of conventional culture that has a reduced turnaround time and a high sensitivity that averages between 68% and 100% when compared to conventional viral culture, and are therefore an excellent tool to rapidly diagnose CMV in BAL and tissue specimens [13, 17]. Polymerase chain reaction (PCR) is the most sensitive assay for detecting CMV in BAL fluid. Alveolar cell immunostaining and PCR have a reported sensitivity of 100% for the diagnosis of CMV pneumonitis, whereas viral culture has a sensitivity of only 85.7% [4]. However, diagnosis of CMV pneumonia should not be based exclusively on PCR, as PCR is considered too sensitive and may detect viral shedding without documented disease.

K.J. Vigil and R.F. Chemaly

Quantification of CMV has been shown to be useful in differentiating between viral shedding and CMV pneumonia in lung transplant recipients [6, 7]. However, the significance in other immunocompromised patients, including patients with hematologic malignancies, has not been studied. CMV antigenemia assays are used to monitor CMV infection. The antigenemia assay is based on the detection of the CMV lower matrix protein pp65 in polymorphonuclear leukocytes by immunostaining with monoclonal antibodies. Results are quantified; patients with a high number of antigenemia-positive leukocytes are at a higher risk for developing CMV disease. Researchers have found CMV antigenemia to be a predictor for development of CMV pneumonia [5, 23]. The development of CMV PCR assays has improved efficiency and sensitivity for direct detection of CMV in various specimens, including blood, plasma, urine, CSF, and biopsy material. Because the CMV viral load in blood correlates with the development of CMV disease, determining the CMV DNA viral load during the initial phase of infection and measuring the rate of increase in the viral load may help identify HSCT recipients who are at risk of developing CMV disease [14].

23.2.4 Treatment 23.2.4.1 Treatment Options Current systemic antiviral agents used to treat CMV infections include ganciclovir, foscarnet, and cidofovir. Therapy for CMV pneumonia includes both ganciclovir and intravenous immunoglobulin. Although this treatment has not been evaluated in a randomized controlled trial and a recent study questioned whether the use of immunoglobulin improves outcome [21], its use is still recommended by experts. The use of ganciclovir is limited by the associated development of neutropenia. Foscarnet is used off-label to treat patients who experience myelosuppression with ganciclovir. However, the use of foscarnet is associated with nephrotoxicity and electrolyte imbalances (i.e., hypokalemia, hypocalcemia, hypomagnesemia, and hypophosphatemia). Cidofovir’s side effects include nephrotoxicity and, occasionally, neutropenia (Table 23.1).

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297

Table 23.1  Recommended treatment and prophylaxis doses, side effects, and resistance mechanisms of available antiviral agents with activity against cytomegalovirus Antiviral agent Recommended doses Common side effects Resistance mechanism Ganciclovir

Foscarnet

Treatment dose:

Hematologic toxicities

5 mg/kg IV q 12 h (induction)

Neurologic toxicity

5 mg/kg IV q 24 h (maintenance)

Abnormal liver function

Prophylaxis dose:

Fever

5 mg/kg IV q 24 h

Rash

Treatment dose:

Nephrotoxicity

90 mg/kg IV q 12 h (induction)

Electrolyte imbalance (hypocalcemia)

90 mg/kg IV q 24 h (maintenance)

Seizures

Prophylaxis dose:

Anemia

Mutations in UL97 or UL54 gene

Mutations in UL54 gene

90 mg/kg IV q 24 h Cidofovir

Valganciclovir

Acyclovir

Treatment dose:

Nephrotoxicity

1–5 mg/kg/week, followed by maintenance every other week

Hematologic adverse effects

Prophylaxis dose:

Hematologic toxicities

900 mg PO daily

Gastrointestinal adverse effects

Prophylaxis dose:

Acute renal failure

500 mg/m IV every 8 h

Neurologic toxicity

Prophylaxis dose:

Thrombotic thrombocytopenic purpura

2

Valacyclovir

2 g/four times daily

Mutations in UL54 gene

Mutations in UL97 or UL54 gene Absence, decrease, or alteration of viral thymidine kinase Absence, decrease, or alteration of viral thymidine kinase

DNA deoxyribonucleic acid, RNA ribonucleic acid

23.2.4.2  Resistance Emergence of resistant CMV strains must be considered when choosing a treatment. Resistance to ­ganciclovir develops from mutations in UL97 (phosphotransferase), UL54 (viral DNA polymerase), or both, whereas resistance to cidofovir and foscarnet develops from mutations in UL54 only. In patients receiving ganciclovir, resistance results exclusively from UL97 in 90% of patients; however, if use of the drug is continued, UL54 mutations may develop, precluding the use of cidofovir secondary to cross-resistance, which is uncommon with foscarnet. Similarly, if UL54-resistant mutations develop in a patient receiving either ganciclovir or cidofovir, cross-resistance precludes the secondary use of the other drug; however, this is not the case with foscarnet [11].

Although it takes weeks to months for resistance to develop, clinicians should be aware that 66% of patients undergoing treatment for CMV pneumonia may show increased CMV antigenemia or viremia, but this is not associated with resistance [26].

23.2.5 Outcome Interestingly, the incidence of fatal CMV pneumonia in HSCT recipients has decreased from 4% in 1997 to 0.8% in 2004 [29]. In patients with leukemia, the associated CMV pneumonia mortality rate is 57%; in patients with lymphoma, it is 30% [5, 25]. A high APACHE II score (>16 at onset of CMV pneumonia) and development of toxicity due to the use of antiviral agents have

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Table 23.2  Incidence, risk factors, and mortality rates reported in patients with hematologic malignancies and cytomegalovirus pneumonia Hematopoietic stem cell Leukemia patients Lymphoma patients transplant recipients Incidence

Allogeneic: 10.0–30.0% autologous: 2.0%

2.9%

1.1%

Risk factors

Old age

Use of lymphocytotoxic chemotherapeutic agents

B-cell non-Hodgkin lymphoma

Graft-versus-host disease Positive serology of the donor

Active disease Advanced-stage disease (stage III/IV) Recurrent disease

Use of granulocyte transfusions from seropositive donors Total-body irradiation Depleted antithymocyte globulins Receipt of T-cell–depleted stem cells Viruria Viremia Mortality rates (%)

0.8–4.0

been shown to be predictors of death in patients with lymphoma and CMV pneumonia [5] (Table 23.2).

23.3 Prevention One of the main goals in treating immunocompromised patients is the prevention of CMV disease; this goal can be accomplished by early detection of the virus DNA in plasma via PCR assays or CMV antigenemia. Preemptive antiviral therapy, when given immediately after detection of CMV in plasma, can prevent the development of end-organ disease and decrease mortality [19]. However, some clinicians favor the use of prophylactic therapy. Ganciclovir has been shown to be effective at preventing the development of CMV pneumonia in the first 100 days posttransplantation [1]. Valganciclovir, an oral prodrug of ganciclovir that has a tenfold greater bioavailability than oral ganciclovir, is also used as prophylactic therapy in high-risk transplant recipients [27]. Maribavir is a benzimidazole riboside with an unnatural L-sugar moiety that inhibits the UL97 kinase, an early viral gene product involved in viral DNA elongation, DNA packaging, and egress

57.0

30.0

or shedding of capsids from viral nuclei; in a phase II study of prophylactic therapy, maribavir was shown to reduce the incidence of CMV infection without the potential side effect of myelosuppression of ganciclovir [32], providing promising results in the future management of CMV disease. However, preliminary data analysis from a phase III study failed to show any significant difference between maribavir and a placebo in reducing the rate of CMV pneumonia in HSCT recipients within 180 days posttransplantation (unpublished data).

References   1. Boeckh M, Gooley TA, Myerson D et  al (1996) Cytomegalovirus pp 65 antigenemia guided early treatment with ganciclovir marrow transplantation: a randomized double blind study. Blood 88:4063–4071   2. Boeckh M, Leisenring WM, Riddell S et al (2003) Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity. Blood 101:407–414   3. Bowden RA, Slichter SJ, Sayers MH et  al (1991) Use of leukocyte-depleted platelets and cytomegalovirus-­ seronegative red blood cells for prevention of primary cytomegalovirus infection after marrow transplant. Blood 78:246–250

23  Cytomegalovirus Pneumonia in Patients with Hematologic Malignancies   4. Cathomas G, Morris P, Pekle K et al (1993) Rapid diagnosis of cytomegalovirus pneumonia in marrow transplant recipients by bronchoalveolar lavage using the polymerase chain reaction, virus culture, and the direct immunostaining of alveolar cells. Blood 81:1909–1914   5. Chemaly RF, Torres HA, Hachem RY et  al (2005) Cytomegalovirus pneumonia in patients with lymphoma. Cancer 104:1213–1220   6. Chemaly RF, Yen-Lieberman B, Castilla EA et  al (2004) Correlation between viral loads of cytomegalovirus in blood and bronchoalveolar lavage specimens from lung transplant recipients determined by histology and immunohistochemistry. J Clin Microbiol 42:2168–2172   7. Chemaly RF, Yen-Lieberman B, Chapman J et  al (2005) Clinical utility of cytomegalovirus viral load in bronchoalveolar lavage in lung transplant recipients. Am J Transplant 5:544–548   8. Crawford SW, Bowden RA, Hackman RC et al (1988) Rapid detection of cytomegalovirus pulmonary infection by bronchoalveolar lavage and centrifugation culture. Ann Intern Med 108:180–185   9. de Medeiros CR, Moreira VA, Pasquini R (2000) Cytomeg­ alovirus as a cause of very late interstitial pneumonia after bone marrow transplantation. Bone Marrow Transplant 26:443–444 10. Demirkazik FB, Akin A, Uzun O et al (2008) CT findings in immunocompromised patients with pulmonary infections. Diagn Interv Radiol 14:75–82 11. Drew WL (2010) Cytomegalovirus resistance testing: pitfalls and problems for the clinician. Clin Infect Dis 50: 733–736 12. Einsele H, Ehninger G, Hebart H et al (1995) Polymerase chain reaction monitoring reduces the incidence of cytomegalovirus disease and the duration and side effects of antiviral therapy after bone marrow transplantation. Blood 86: 2815–2820 13. Emanuel D, Peppard J, Stover D et al (1986) Rapid immunodiagnosis of cytomegalovirus pneumonia by bronchoalveolar lavage using human and murine monoclonal antibodies. Ann Intern Med 104:476–481 14. Emery V, Sabin C, Cope A et al (2000) Application of viral load kinetics to identify patients who developed cytomegalovirus disease after transplantation. Lancet 355:2032–2036 15. Enright H, Haake R, Weisdorf D et al (1993) Cytomegalovirus pneumonia after bone marrow transplantation.Risk factors and response to therapy. Transplantation 55:1339–1346 16. Gasparetto EL, Ono SE, Escuissato D et  al (2004) Cytomegalovirus pneumonia after bone marrow transplantation: high resolution CT findings. Br J Radiol 77:724–727 17. Gleaves CA, Smith TF, Shuster EA et al (1985) Comparison of standard tube and shell vial cell culture techniques for the detection of cytomegalovirus in clinical specimens. J Clin Microbiol 21:217–221 18. Kim EA, Lee KS, Primack SL et al (2002) Viral pneumonias in adults: radiologic and pathologic findings. Radiographics 22:S137–S149

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19. Ljungman P, Aschan J, Lewensohn-Fuchs I et  al (1998) Results of different strategies for reducing cytomegalovirusassociated mortality in allogeneic stem cell transplant recipients. Transplantation 66:1330–1334 20. Ljungman P, Griffiths P, Paya C (2002) Definitions of ­cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis 34:1094–1097 21. Machado CM, Dulley FL, Boas LS et al (2000) CMV pneumonia in allogeneic BMT recipients undergoing early treatment of pre-emptive ganciclovir therapy. Bone Marrow Transplant 26:413–417 22. Meyers JD, Flournoy N, Thomas ED (1986) Risk factors for cytomegalovirus infection after human marrow transplantation. J Infect Dis 153:478–488 23. Meyers JD, Ljungman P, Fisher LD (1990) Cytomegalovirus excretion as a predictor of cytomegalovirus disease after marrow transplantation: importance of cytomegalovirus viremia. J Infect Dis 162:373–380 24. Nakamura R, Battiwalla M, Solomon S et al (2004) Persisting posttransplantation cytomegalovirus antigenemia correlates with poor lymphocyte proliferation to cytomegalovirus antigen and predicts for increased late relapse and treatment failure. Biol Blood Marrow Transplant 10:49–57 25. Nguyen Q, Estey E, Raad I et  al (2001) Cytomegalovirus pneumonia in adults with leukemia: an emerging problem. Clin Infect Dis 32:539–545 26. Nichols WG, Corey L, Gooley T et al (2001) Rising pp 65 antigenemia during preemptive anticytomegalovirus therapy after allogeneic hematopoietic stem cell transplantation: risk factors, correlation with DNA load, and outcomes. Blood 97:867–874 27. Reusser P (2002) Management of viral infections in immunocompromised cancer patients. Swiss Med Wkly 132: 374–378 28. Staras SA, Dollard SC, Radford KW et  al (2006) Seroprevalence of cytomegalovirus infection in the United States, 1988-1994. Clin Infect Dis 43:1143–1151 29. Torres HA, Aguilera E, Safdar A et  al (2008) Fatal cytomegalovirus pneumonia in patients with hematologic malignancies: an autopsy-based case-control study. Clin Microbiol Infect 14:1160–1166 30. Torres HA, Kontoyiannis DP, Aguilera EA et  al (2006) Cytomegalovirus infection in patients with lymphoma: an important cause of morbidity and mortality. Clin Lymphoma Myeloma 6:393–398 31. Wingard JR, Chen DY, Burns WH et  al (1988) Cytomegalovirus infection after autologous bone marrow transplantation with comparison to infection after allogeneic bone marrow transplantation. Blood 71:1432–1437 32. Winston DJ, Young JA, Pullarkat V (2008) Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study. Blood 111:5403–5410

 

Herpes Simplex Virus Pneumonia in Patients with Hematologic Malignancies

24

Jharna N. Shah and Roy F. Chemaly

Contents

24.1 Introduction

24.1 Introduction............................................................. 301

Herpes simplex virus (HSV) is known to cause mucocutaneous disease in patients with hematologic malignancies [11, 42]. HSV most commonly leads to orofacial, genital, and esophageal lesions, and less commonly can lead to hepatitis, meningitis, encephalitis, bone marrow suppression, and pneumonia [22, 38, 42]. HSV pneumonia is very rare and has been reported in about 3% of the patients with hematologic malignancies and in about 5% of patients who have undergone hematopoietic stem cell transplant (HSCT) (these patients will be referred to as ‘HSCT patients’ in the chapter) without prophylaxis [56]. After acyclovir prophylaxis was implemented in patients with a HSCT, the incidence of HSV excretion dropped to 2.5% [49], while HSV pneumonia has been reported in less than 1% of all pneumonias developing after HSCT [16]. Cytomegalovirus (CMV) has been implicated as the most common agent in nonbacterial pneumonias in patients with hematologic malignancies and in patients who have undergone HSCT [33, 46]. However, HSV has been demonstrated as the most common pathogen in bronchial samples of patients with severe respiratory distress who have been treated with assisted ventilation [54]. Before the 1990s, cases of HSV pneumonia were characterized as “idiopathic pneumonia” because of insufficient diagnostic testing or simply lack of awareness of HSV as a causative agent in lower respiratory tract disease [46]. HSV pneumonia is diagnosed most frequently in the setting of severe immunosuppression [14, 16, 17, 27, 60, 64]. Studies involving HSV pneumonia have been conducted frequently in patients who have undergone HSCT and less frequently in other types of immunocompromised patients, such as those with

24.2 Incidence and Transmission................................... 303 24.3 Pathogenesis............................................................ 303 24.3.1 Pathogenesis in Humans........................................... 303 24.3.2 Animal Models......................................................... 303 24.4 Risk Factors............................................................. 304 24.5 Clinical Features..................................................... 304 24.5.1 Clinical Manifestations............................................. 304 24.5.2 Coinfections.............................................................. 305 24.5.3 Differential Diagnosis............................................... 305 24.6 Diagnosis.................................................................. 305 24.6.1 Virus Isolation........................................................... 305 24.6.2 Gene Amplification................................................... 305 24.6.3 Lung Biopsy/Cytology............................................. 306 24.6.4 Radiology.................................................................. 306 24.7 Management............................................................ 306 24.7.1 Treatment.................................................................. 306 24.7.2 Prophylaxis............................................................... 306 24.7.3 Resistance to Antivirals............................................ 309 24.7.4 Vaccine...................................................................... 309 24.8 Outcome................................................................... 309 24.9 Prognosis.................................................................. 309 References............................................................................ 310

J.N. Shah Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, P.O. Box 402, Houston, TX 77030, USA e-mail: [email protected] R.F. Chemaly (*) Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, P.O. Box 402, Houston, TX 77030, USA e-mail: [email protected]

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_24, © Springer-Verlag Berlin Heidelberg 2011

301

302 

J.N. Shah and R.F. Chemaly

hematologic malignancies, solid tumors, burns, critical illnesses, or acquired immune deficiency syndrome (AIDS) [3, 8, 12, 17, 42, 54]. Respiratory involvement is seen most commonly with herpes simplex virus-1 (HSV-1) [40, 43, 56], but some cases of herpes simplex virus-2 (HSV-2) have been reported [13, 25]. Table 24.1  Studies and case reports on HSV pneumonia No. Author, No. of cases Type of immunoyear compromised population

In this chapter, we will focus on incidence and transmission, pathogenesis, risk factors, clinical features, diagnosis, and management for HSV pneumonia in patients with hematologic malignancies and HSCT patients as well as outcome and prognosis. Table  24.1 summarizes the outcomes in studies and

Management

Outcome

1

Meyers 1982 [46]

10 Nonbacterial pneumonia.

10 weeks s/p HSCT, GVHD

Not enough information available.

All patients died.

2

Ramsey 1982 [56]

20 Autopsy cases

HM, 2 months s/p HSCT, nonHM; on chemotherapy, radiotherapy

None were on prophylaxis. No treatment given.

All patients died of respiratory failure. Pneumonia to death within 24 days (mean)

3

Ljungman 1990 [40]

3 Acyclovirresistant HSV-1 pneumonia

Early HSCT period, GVHD

Case 1: Px: ACV 250 mg/m2 Q12h × 30 days post-HSCT; Rx: ACV 500 mg/m2 Q12h + IV Vidarabine 10 mg/kg

Patient 1: Died on day 70.

Case 2: Px: ACV 250 mg/m2 Q8h × 29 days; Rx: ACV × 250 mg/m2 Q8h

Patient 2: Died on day 100.

Case 3: Px-ACV 500 mg/m2 Patient 3: Died on day 131. Q8h × 25 days; Rx- Ganciclovir 5 mg/kg Q8h × 19 days, ACV 250 mg/m2 Q8h × 39 days Lymphoma, solid organ transplants, AIDS, SLE

Px- N/A

Ferrari 2005 1 [23]

B-cell ALL on chemotherapy

Px-None

10

Gasparetto 2005 [25]

3 HSV-2 pneumonia

HSCT (two early-phase, one late-phase)

Px- 1 pt on ACV 200 mg Q12h; Two patients improved, one died of respiratory Rx- ACV 500 mg Q8h failure in 2 weeks

11

Frangoul 2007 [24]

2 ACV-resistant HSV-1 pneumonia

HSCT, GVHD

Px- PO ACV 600 mg/m2 Q12h or IV ACV 250 mg/m2 Q12h; Rx- IV ACV 250 mg/m2 Q8h; Foscarnet 60 mg/kg Q12h – then 90 mg/kg Q12h

Died on day 110 from respiratory failure.

12

Aisenberg 2009 [3]

45 HSV pneumonia (6: proven, 25: probable, 14: possible)

Solid tumors on steroids and radiotherapy

Px-None

Ten (22%) died: four treated, six untreated).

5

9

Schuller 1993 [60]

15 HSV-1 pneumonia

Rx-ACV × 17 days (mean)

Rx-ACV 10 mg/kg Q8h on day 31; later Px- Valacyclovir

Rx-ACV (n = 17), Valacyclovir (n = 7), Famciclovir (n = 1) × 13 days (mean)

33% Died (n = 5) from sepsis (2), respiratory failure (2), dehiscence of tracheal anastomosis after lung transplant (1). Noninvasive ventilation needed→ infection resolved by day 42.

ACV Acyclovir, ALL acute lymphocytic leukemia, GVHD graft-versus-host-disease, HM hematologic malignancy, IV intravenous, N/A not available, PO oral, Px prophylaxis, Q8h every 8 hourly, Q12h every 12 hourly, Rx treatment, s/p HSCT status post-hematopoietic stem cell transplant

24  Herpes Simplex Virus Pneumonia in Patients with Hematologic Malignancies

case reports of patients with HSV pneumonia who have hematologic malignancies and HSCT patients.

24.2 Incidence and Transmission HSV belongs to the Herpesviridae family, which comprises HSV-1, HSV-2, varicella zoster virus, CMV, Epstein-Barr virus, human herpes viruses 6 and 7, and Kaposi’s sarcoma-associated herpesvirus (type 8) [37, 66]. HSV (types 1 and 2) belongs to the subfamily Alphaherpesvirinae [37, 66]. HSV-1 and -2 are ubiquitous and contagious, and they are transmitted horizontally during close contact with an infected person who is shedding the virus from the skin, saliva, or secretions from the genitals [22, 38]. Asymptomatic viral shedding and transmission are known to occur, especially in HSV-2 infections [38]. HSV-1 is usually acquired orally during childhood, but may also be transmitted sexually [38]. HSV-2 is transmitted primarily by sexual contact [38]. The virus is reactivated secondary to triggers such as psychological stress; fatigue; exposure to heat, cold, or sunlight; menstruation; sexual intercourse; fever; immunosuppression; corticosteroid administration; laser surgery; local tissue trauma; nerve damage; and change in antiviral activity of the saliva [22]. About 80% of adult patients with hematologic malignancies are HSV seropositive [62]. HSV reactivates in about 70–80% of seropositive patients [29]. The incidence of mucocutaneous lesions among seropositive patients with leukemia has been reported to range from 15% (among CLL patients treated with fludarabine) to 90% (in patients with acute leukemia or HSCT) [5, 11, 42, 57, 58]. HSCT patients more commonly show HSV reactivations, especially within the first 4 weeks of the transplant, while primary infections are unusual [45].

24.3 Pathogenesis 24.3.1 Pathogenesis in Humans HSV is a double-stranded deoxyribonucleic acid (DNA) virus that measures approximately 200 nm in diameter and contains a linear, double-stranded DNA

303

core enclosed within an icosahedral protein capsid, covered by a tegument and a glycoprotein-containing envelope [37, 44, 50, 66, 68]. Initial exposure to herpesviruses often leads to viral invasion of epithelial cells and intracellular replication at the site of primary exposure [50, 66, 68]. Following primary infection, the virus ascends in a retrograde manner through the periaxonal sheath of sensory nerves to the trigeminal, cervical, lumbosacral, or autonomic ganglia of the host’s nervous system [50, 66, 68]. The virus replicates and remains dormant for life. The trigeminal and sacral ganglia are the most common locations for HSV-1 and HSV-2 latency, respectively [22]. Pulmonary involvement in patients with hematologic malignancies may be focal or diffuse [56]. Focal disease may begin as mucocutaneous/ororpharyngeal disease and continue down to the lower respiratory tract (contiguous spread), whereas diffuse pneumonia is associated with hematogenous dissemination [56]. Concomitant/preceding HSV in pharynx, urine, liver, or genitals has been reported [27, 52, 56]. HSV-1 pneumonia occurs through aspiration or contiguous spread, and HSV-2 pneumonia is caused by hematogenous spread [44]. HSV pneumonia is an intrabronchial process [27]. Focal or diffuse ulcers in the tracheobronchial epithelium can lead to necrotizing herpetic tracheitis, as was found in autopsy specimens of patients with hematologic malignancies [56]. HSV has been shown to be less replicative than CMV is in alveolar macrophages, thus suggesting the role of altered macrophage function in the development of HSV pneumonia [20]. However, an agedependent protective role against disseminated HSV disease has also been demonstrated [47].

24.3.2 Animal Models Studies in animal models have attempted to elucidate the pathogenesis of HSV pneumonia [1, 2, 19]. Reactive oxygen/nitrogen species (RONS) has been implicated in the development of viral pneumonitis [19]. Intranasal infection of mice with HSV-1 resulted in rapid development of pneumonia and decreased lung compliance, and was associated with elevated expression of inducible nitrogen oxide synthase (iNOS) protein and increased nitrotyrosine adduct formation

304 

in the lungs of infected mice. When these mice were treated with a NOS inhibitor, pneumonitis was almost completely suppressed, recovery of inflammatory cells from bronchoalveolar lavage fluid was decreased, and both lung compliance and survival were improved [1]. Animal models have also demonstrated that graftversus-host disease (GVHD) is an important factor in the development of HSV pneumonitis. Allogeneic transplant mice with GVHD developed more severe pneumonitis after intranasal HSV-1 infection than did control mice without GVHD. The former group also showed an enhanced transforming growth factor-1 (TGF-1) production, which was implicated as a more important factor than the pulmonary viral load [2].

24.4 Risk Factors Several risk factors have been identified that increase the risk of HSV pneumonia in patients with hematologic malignancies. HSV pneumonia is generally a result of reactivation of a latent HSV infection [42, 50, 56, 68]. Several triggers, such as stress, corticosteroid administration, and immunosuppression, may cause reactivation of the virus [22]. HSV affects squamous epithelial cells, and factors promoting squamous metaplasia such as smoking, trauma, burns, and tracheal trauma from intubation may predispose a patient to develop HSV pneumonia [27, 51, 52, 56, 60]. Intubation of a patient with oral herpes can trigger reactivation or cause a lower respiratory tract infection through direct inoculation or aspiration [8, 56]. Thus, intubated patients who fail to be weaned off the ventilator should be evaluated for HSV pneumonia, as it is an often under-recognized cause of nonbacterial pneumonia [46]. Patients with hematologic malignancies who are undergoing aggressive chemotherapy and treatment with corticosteroids are at increased risk of HSV, as impairment of cellular immunity is a risk factor for HSV infections and reactivations [57]. Persistent and severe T-cell depletion is seen after aggressive chemotherapy and after administration of monoclonal antibodies (e.g., anti-CD52 antibody, alemtuzumab) [32, 55] and has been identified as a predictor for HSV infections [15, 17, 64]. HSCT patients are at greater risk of developing HSV infections, as chemotherapy and radiotherapy

J.N. Shah and R.F. Chemaly

used before HSCT may damage the normal upper respiratory mucosa and predispose the patient to direct spread of the virus to the lower respiratory tract [56]. These agents may also trigger reactivation of the virus [34]. The use of cyclophosphamide, busulfan, carmustine, and total body irradiation in conditioning regimens has been seen in patients with HSV pneumonia [24, 46]. HSV reactivation occurs most commonly in the first month after HSCT; however, late-onset HSVassociated pneumonia has also been reported [35]. Additionally, patients with hematologic malignancies are often neutropenic [absolute neutrophil count (ANC) <500/mL] secondary to the chemotherapy. Neutropenia has also been observed in patients with hematologic malignancies who have HSV pneumonia [56]. GVHD as a risk factor for HSV disease in HSCT patients and severity of GVHD as a predictor of nonresponsiveness to antiviral therapy has also been reported [16]. In some studies, the immunosuppressive effect of multiple blood transfusions has also been implicated in the development of HSV pneumonia [64]. Patients undergoing solid organ transplant (SOT) are at risk of developing HSV pneumonia. The incidence of HSV pneumonia in SOT patients is about 5%, while mortality of up to 100% has been reported, especially in liver transplant recipients [4, 31, 39].

24.5 Clinical Features 24.5.1 Clinical Manifestations The clinical manifestations of HSV pneumonia are nonspecific [3, 18, 40, 56]. In HSCT patients, symptomatic disease occurs 2–3 weeks after transplant when mucosal damage is maximal from radiotherapy and chemotherapy [23]. HSV infections can manifest with nonrespiratory symptoms before showing signs of pulmonary involvement [23, 54]. Nonrespiratory manifestations of HSV reactivation infrequently include oral mucocutaneous lesions. Esophagitis and rarely, genital lesions may also precede lower respiratory involvement [54, 56]. Respiratory symptoms of HSV pneumonia include low-grade fever, cough, dyspnea, rales, hypoxemia, tachypnea, intractable wheezing, or chest pain [56]. Hemoptysis may also be present, secondary to tracheitis [63].

24  Herpes Simplex Virus Pneumonia in Patients with Hematologic Malignancies

Patients with HSV pneumonia may typically either demonstrate worsening respiratory status that is unresponsive to prolonged antibacterial treatment and may require intubation or patients may already be intubated, and may worsen and fail to wean off the ventilator. Persistent low-grade fevers and unimpressive infiltrates on imaging with leukocytosis would indicate a nonbacterial cause. Interstitial lung involvement in HSV pneumonia is characterized by worsening oxygenation [evident from low pO2 with a high fraction of inspired oxygen (FiO2)], decrease in diffusing capacity of the lung for carbon monoxide (DLCO), and an increase in alveolar-arterial (A-a) gradient over 30 [18]. HSV pneumonia is often complicated by acute respiratory distress syndrome (ARDS) and respiratory failure, and mechanical ventilation is often needed, especially in untreated patients [56].

305

24.6 Diagnosis HSV pneumonia should be suspected in immunocompromised patients who are not on acyclovir prophylaxis, who are intubated with worsening oxygenation, and who have not been weaned off a ventilator despite aggressive management [18, 23, 54]. There are no standardized diagnostic criteria for HSV pneumonia. The definitive diagnosis of HSV pneumonia can be made by isolating the virus from respiratory secretions, bronchoalveolar lavage samples, and lung tissue and by demonstrating viral cytopathic effects on histopathology [18, 42, 56].

24.6.1 Virus Isolation 24.5.2 Coinfections Pulmonary coinfections may often be present and may complicate the diagnosis of patients with HSV pneumonia. Up to 65% of the patients with HSV pneumonia may have copathogens, such as CMV, Candida, Aspergillus, Pneumocystis jirovecii, mycobacterium avium intracellulare (MAI), and other bacteria [3, 40, 56]. Patients are often treated preemptively for bacterial pneumonia before diagnosis of HSV has been confirmed, which may lead to a delay in initiation of HSV-specific treatment.

24.5.3 Differential Diagnosis In an immunocompromised host, the most common infectious cause of pneumonia is bacterial, which presents with acute deterioration and significant hypoxemia. Subacute presentation suggests involvement of atypical bacterial, viral, or fungal organisms, while chronic presentation suggests fungal or mycobacterial infection. Pneumocystis jirovecii, CMV, respiratory syncytial virus, and influenza pneumonia are the most important organisms in the differential diagnosis of diffuse bilateral infiltrates, accompanied by significant oxygen defect (A-a gradient >30) [18]. Noninfectious causes may include drug toxicity, pulmonary hemorrhage, GVHD, and heart failure.

Shell-vial culture for virus isolation and demonstration of cytopathic effects are methods commonly used to diagnose HSV. The sensitivity of these methods has been reported to be 57%, with a specificity of 100% [10]. The shell-vial culture yields results in 48 h [62]. Rapid antigen detection by direct immunofluorescence is also often employed for early detection of HSV, with sensitivity and specificity of about 80% and 100%, respectively [10].

24.6.2 Gene Amplification Polymerase chain reaction (PCR) for HSV DNA is more rapid and more sensitive than conventional culture, shell-vial culture, and antigen-detection methods [61]. However, PCR is unable to distinguish between active disease and contamination from oral cavity [61]. Serology is useful for identifying patients with seropositive HSV before induction chemotherapy or before HSCT [62]. Detection of immunoglobulin M (IgM) antibody and demonstration of an increase in immunoglobulin G (IgG) titers can be useful in patients with an active infection [59]. However, it takes several weeks to mount a significant antibody response and depends on a functioning immune system. Thus, serology is less useful with HSV pneumonia when a rapid diagnosis is necessary [30, 59]. Additionally, a

306 

fourfold increase in titers is helpful for diagnosing primary HSV infection; however, such an increase may not be observed in recurrent infections [30].

24.6.3 Lung Biopsy/Cytology Nonspecific fibroproliferative pattern and tissue necrosis are demonstrated on lung biopsy in patients with HSV pneumonia [23]. However, lung biopsy is rarely performed in patients with cancer because of increased complications, inconsistent diagnosis, and questionable reliability [56, 64]. A few scattered ulcers in the trachea or a severe ulcerative process resulting in an obstructed and inflamed tracheobronchial membrane may be evident on direct examination [27]. Parenchymal involvement begins in lungs, adjacent to the terminal and respiratory bronchioles, but may extend throughout the lobule [33, 56]. Diffuse alveolar damage comprising interstitial lymphocyte infiltration, air space hemorrhage, intraalveolar fibrinous exudate, edema, fibroblast proliferation, type 2 hyperplasia, and hyaline membrane formation is often evident [33, 56]. Cytology demonstrates multinucleated giant cells with enlarged, molded, basophilic nuclei of groundglass appearance or cells with large intranuclear eosinophilic inclusions (“owl-eyes”-Cowdry type A inclusion bodies) in the alveolar or bronchial cells and macrophages obtained in washings or biopsies [56].

24.6.4 Radiology Radiologic changes in HSV pneumonia are often nonspecific [3, 6, 36, 65]. These changes are similar to those seen in other viral pneumonias and are not different from those seen in immunocompetent patients [65]. Chest x-ray may be near normal early in the disease [18]. In advanced disease, however, focal, multifocal, or diffuse bilateral opacities with predominantly mixed (partly airspace consolidation and partly interstitial) or airspace consolidation is often seen [18, 65]. Less frequently seen are unilateral consolidation, large atelectasis, and pleural effusion [56, 65]. High-resolution computed tomography (CT) scans are used for better delineation of the disease process [25]. HSV-1 shows multifocal, subsegmental, and ground-glass attenuation with consolidation, reticular, and nodular opacities; HSV-2 demonstrates diffuse

J.N. Shah and R.F. Chemaly

alveolar damage, small centrilobular nodules, and interstitial pneumonia [6, 25]. Large nodules and pleural effusions are also seen [6, 25].

24.7 Management 24.7.1 Treatment Acyclovir is the most widely used and effective therapy for HSV pneumonia [11, 68]. However, empiric therapy based on suspicion of HSV pneumonia has not been recommended [18]. HSV-specific treatment of pneumonia has been reported to prevent progression to respiratory failure and mortality in patients with hematologic malignancies and in HSCT patients [23, 25, 35]. Improvement in oxygenation status can be seen in 3–5 days, and patients may be able to be weaned off the ventilator [18]. However, treatment has showed no significant effect on mortality, duration of mechanical ventilation, length of intensive care unit (ICU) stay, or length of hospitalization in a group of immunocompromised patients (patients with lymphoma, with solid-organ transplants, or with AIDS or systemic lupus erythematosus [SLE]) as compared to immunocompetent patients [60]. HSV is susceptible to acyclovir, valacyclovir, famciclovir, foscarnet, cidofovir, and, to a lesser extent, ganciclovir [37]. Table 24.2 shows the mechanisms of action, recommended dosages, and mechanisms of resistance for these drugs. Foscarnet is used to treat acyclovir-resistant strains. However, strains resistant to foscarnet and acyclovir are now being reported [7]. Cidofovir is the only drug used to treat double-resistant HSV [42], although use of cidofovir is associated with significant renal ­toxicity [7]. A significant proportion of patients with HSV pneumonia may have concomitant bacterial pneumonia [3, 40, 56]. Thus, empirical broad-spectrum antibiotic therapy that includes an anti-staphylococcal drug can be used in patients with progressive HSV pneumonia who are unresponsive to antiviral therapy.

24.7.2 Prophylaxis HSV pneumonia accounted for 9% of pneumonias in HSCT patients, prior to acyclovir prophylaxis [56]. Prophylaxis of HSV infection has led to decreased

Synthetic purine nucleoside analog with in vitro and in vivo inhibitory activity against HSV-1, HSV-2, VZV

Same as acyclovir

Same as acyclovir

Acyclovir

Valacyclovir

Famciclovir

500 mg BID

500 mg BID × 3–5 weeks with chemotherapy or after HSCT (longer in children with acute leukemia

500 mg BID × 10 days

The active ingredient is acyclovir. Same as acyclovir, better absorption allows less frequent dosing.

250 mg/m2 or 5 mg/kg IV Q12h, or 200 mg TID to 800 mg BID

500 mg/m2 or 10 mg/kg IV Q12h × 14–21 days

500 mg BID × 10 days

Prophylaxis

Doses for pneumonia

Same as acyclovir.

Affinity for viral enzyme thymidine kinase (TK) leads to (1) competitive inhibition of viral DNA polymerase, (2) incorporation into and termination of the growing viral DNA chain, and (3) inactivation of the viral DNA polymerase. Metabolized by kidneys.

Table 24.2  Antiviral drugs used in HSV pneumonia Drug Susceptibility Mechanism of action

(continued)

Acute retinal necrosis, genital HSV, hepatitis B Same as acyclovir Headache, paresthesia, migraine, nausea, vomiting diarrhea, hematologic, liver dysfunction, carcinogenic

HZV, mucocutaneous HSV in HIV, recurrent genital HSV

Acute retinal Recurrent genital necrosis, CMV HSV, herpes labialis, HZV, VZV infection and prophylaxis, nongenital HSV Same as acyclovir

Acute retinal necrosis, eczema herpeticum, HSV proctitis, meningitis, hepatitis, respiratory and ophthalmic infections; HZV auricularis and encephalitis; herpetic whitlow; VZV prophylaxis, pneumonia and transverse myelitis, viral encephalitis

Non-FDAlabeled indications

TTP/HUS, neurologic effects, renal impairment

FDA-labeled indications Congenital herpes simplex, HSV encephalitis, genital HSV, herpes labialis, mucocutaneous HSV infections, herpes zoster, varicella

Mechanism of Resistance Qualitative and quantitative changes in the viral TK and/or DNA polymerase

Nausea, vomiting, diarrhea, headache, confusion, coma, hematologic dysfunction, liver failure, renal failure, rash

Side effects

24  Herpes Simplex Virus Pneumonia in Patients with Hematologic Malignancies 307

In vitro against CMV, HSV-1, HSV-2

Cidofovir

Side effects

Renal impairment, electrolyte imbalance, seizures, fever, nausea, vomiting, diarrhea, headache, anemia

Renal impairment, neutropenia, decreased intraocular pressure, anterior uveitis/iritis, metabolic acidosis

Prophylaxis

N/A

N/A

Doses for pneumonia 60 mg/kg IV Q12h, or 40 mg/kg IV Q8h × 7–21 days or until complete healing

5 mg/kg once a week × 2 weeks, then once every 2 weeks combined with probenecid and hydration

Mechanism of action

Selective inhibition at the pyrophosphatebinding site on virus-specific DNA polymerases at concentrations that do not affect cellular DNA polymerases

Suppresses CMV replication by selective inhibition of viral DNA synthesis

Condyloma acuminatum

Intravitreal use in CMV retinitis, CMV pneumonia, HSV keratitis

CMV-retinitis s in AIDS patients, acyclovir-resistant mucocutaneous HSV

Resistance due to DNA polymerase mutations have emerged

Resistance to CMV retinitis in cidofovir has AIDS been selected for in the laboratory setting and occurs through mutations in the viral DNA polymerase. In vivo resistant strains have been reported

Non-FDAlabeled indications

FDA-labeled indications

Mechanism of Resistance

AIDS Acquired immune deficiency syndrome, BID twice a day, CMV cytomegalovirus, HIV human immunodeficiency virus, HSCT hematopoietic stem cell transplant, HSV human herpes simplex virus, IV intravenous, N/A not available, Q12h every 12 hourly, TID thrice a day, TTP/HUS thrombotic thrombocytopenic purpura, VZV Varicella Zoster virus

Activation (phosphorylation) by thymidine kinase or other kinases NOT required, hence, is active in vitro against HSV TK deficient and CMV UL97 mutants

Foscarnet

Table 24.2  (continued) Drug Susceptibility

308  J.N. Shah and R.F. Chemaly

24  Herpes Simplex Virus Pneumonia in Patients with Hematologic Malignancies

prevalence of HSV pneumonia (less than 2% of HSCT recipients) [9, 41, 49]. Antiviral drug prophylaxis is not recommended in HSV-seronegative leukemic patients during chemotherapy or after SCT, since primary HSV infection in these patients is unusual [62]. In HSV-seropositive patients, antiviral drug prophylaxis has been shown to prevent the development of active HSV disease and to reduce mortality rates [29, 69]. Antiviral drug prophylaxis is part of the standard management at many cancer centers for patients with hematologic malignancies undergoing chemotherapy or for patients undergoing HSCT [62, 63, 67, 69]. Acyclovir has been the most common antiviral drug used [28]. However, newer antivirals such as valaciclovir and famciclovir are also active against HSV and have an oral bioavailability three to five times superior to that of oral acyclovir [53, 62]. Both of these agents are used to prevent HSV reactivation during induction chemotherapy for leukemia or after HSCT [49]. Prophylaxis should be given for 3–5 weeks, after the start of chemotherapy or during the pre-engraftment stage in the first month after HSCT [58, 62, 63, 67]. Children, allogeneic HSCT patients who develop GVHD, or patients who require immunosuppressant treatment should receive prolonged prophylaxis [62].

24.7.3 Resistance to Antivirals Long-term prophylaxis with acyclovir in HSCT patients appears to prevent the emergence of drugresistant HSV disease [21]. However, several centers have reported increased incidence of acyclovir-resistant HSV disease, especially in patients who have undergone unrelated HSCT or HLA-mismatched transplant patients with GVHD [16, 40]. Acyclovir resistance is associated with serious morbidity and mortality [7, 16]. Poor response to acyclovir indicates possible resistance, and the patient should be promptly switched to foscarnet or cidofovir [7, 16]. Activation of acyclovir, ganciclovir, valacyclovir, or famciclovir requires initial phosphorylation by viral thymidine kinase (TK) [37]. Resistance to acyclovir can be caused by lack of TK, altered TK, or TK strains with mutations in viral DNA polymerase [37]. TK-negative mutants may cause severe disease in infants and immunocompromised adults [37]. Crossresistance between acyclovir and foscarnet results from their interaction at the same site on HSV DNA

309

polymerase; however, susceptibility to cidofovir is unaffected by the same viral mutation [26].

24.7.4 Vaccine There is no licensed effective vaccine for HSV [37].

24.8 Outcome Patients with HSV pneumonia can require mechanical ventilation and prolonged hospitalization [64]. Mortality in immunocompetent patients has been reported to be about 27% [54]. However, patients with hematologic malignancies and HSCT patients may have high mortality rates (up to 75–100%), if left untreated [46, 56]. Patients with solid tumors and patients with solid-organ transplants have mortality rates that range from 20% to 100%, with a higher percentage of mortality after liver transplants [3, 4, 31]. Severe respiratory distress necessitating mechanical ventilation or worsening respiratory status on a ventilator is often seen in untreated patients with HSV pneumonia, and ARDS or respiratory failure may occur without treatment [54, 56, 64]. Damage to lung function has not been reported in patients that recover from the infection.

24.9 Prognosis The prognosis of patients with HSV pneumonia depends on the immunologic status of the patient and the type of underlying disease [27]. In immunocompetent hosts, HSV pneumonia is not necessarily a fatal disease [48]. In immunocompromised patients, however, HSV pneumonia can lead to respiratory failure and the need for mechanical ventilation or failure to wean off the ventilator and subsequent mortality [18, 24, 25, 27, 40, 56]. Although rare, HSV pneumonia should be considered in neutropenic hematologic patients undergoing chemotherapy with “suggestive” radiologic findings who have not improved after conventional antibacterial and/or antifungal treatments [18, 24, 25, 27, 40, 56].

310 

References   1. Adler H, Beland JL, Del Pan NC et al (1997) Suppression of herpes simplex virus type 1 (HSV-1)-induced pneumonia in mice by inhibition of inducible nitric oxide synthase (iNOS, NOS2). J Exp Med 185:1533–1540   2. Adler H, Beland JL, Kozlow W et al (1998) A role for transforming growth factor-beta1 in the increased pneumonitis in murine allogeneic bone marrow transplant recipients with graft-versus-host disease after pulmonary herpes simplex virus type 1 infection. Blood 92:2581–2589   3. Aisenberg GM, Torres HA, Tarrand J et  al (2009) Herpes simplex virus lower respiratory tract infection in patients with solid tumors. Cancer 115:199–206   4. Allen KA, Markin RS, Rennard SI et  al (1989) Bronchoalveolar lavage in liver transplant patients. Acta Cytol 33:539–543   5. Anaissie EJ, Kontoyiannis DP, O’Brien S et  al (1998) Infections in patients with chronic lymphocytic leukemia treated with fludarabine. Ann Intern Med 129:559–566   6. Aquino SL, Dunagan DP, Chiles C et  al (1998 Sep–Oct) Herpes simplex virus 1 pneumonia: patterns on CT scans and conventional chest radiographs. J Comput Assist Tomogr 22(5):795–800   7. Blot N, Schneider P, Young P et al (2000 Oct) Treatment of an acyclovir and foscarnet-resistant herpes simplex virus infection with cidofovir in a child after an unrelated bone marrow transplant. Bone Marrow Transplant 26(8):903–5   8. Bruynseels P, Jorens PG, Demey HE (2003 Nov 8) Herpes simplex virus in the respiratory tract of critical care patients: a prospective study. Lancet 362(9395):1536–41   9. Burns WH (1999) Advances in the control of cytomegalovirus disease in bone marrow transplant patients. Cancer Treat Res 101:185–201, Review 10. Burrows J, Nitsche A, Bayly B et al (2002 Jun 9) Detection and subtyping of Herpes simplex virus in clinical samples by LightCycler PCR, enzyme immunoassay and cell culture. BMC Microbiol 2:12 11. Bustamante CI, Wade JC (1991 Oct) Herpes simplex virus infection in the immunocompromised cancer patient. J Clin Oncol 9(10):1903–15 12. Byers RJ, Hasleton PS, Quigley A et  al (1996 Nov) Pulmonary herpes simplex in burns patients. Eur Respir J 9(11):2313–7 13. Calore EE (2002 Dec) Herpes simplex type 2 pneumonia. Braz J Infect Dis 6(6):305–8 14. Camps K, Jorens PG, Demey HE et al (2002 Oct) Clinical significance of herpes simplex virus in the lower respiratory tract of critically ill patients. Eur J Clin Microbiol Infect Dis 21(10):758–9 15. Chakrabarti S, Pillay D, Ratcliffe D et al (2000) Resistance to antiviral drugs in herpes simplex virus infections among allogeneic stem cell transplant recipients: risk factors and prognostic significance. J Infect Dis 181:2055–8 16. Chen CS, Boeckh M, Seidel K et al (2003 Sep) Incidence, risk factors, and mortality from pneumonia developing late after hematopoietic stem cell transplantation. Bone Marrow Transplant 32(5):515–22 17. Cook CH, Yenchar JK, Kraner TO et al (1998 Oct) Occult herpes family viruses may increase mortality in critically ill surgical patients. Am J Surg 176(4):357–60

J.N. Shah and R.F. Chemaly 18. Cunha BA, Eisenstein LE, Dillard T et  al (2007 Jan-Feb) Herpes simplex virus (HSV) pneumonia in a heart transplant: diagnosis and therapy. Heart Lung 36(1):72–8 19. Davis I, Matalon S (2001) Reactive Species in Viral Pneumonitis: Lessons From Animal Models. News Physiol Sci 16:185–190 20. Drew WL, Mintz L, Hoo R et al (1979 Feb) Growth of herpes simplex and cytomegalovirus in cultured human alveolar macrophages. Am Rev Respir Dis 119(2):287–91 21. Erard V, Wald A, Corey L et al (2007 Jul 15) Use of long-term suppressive acyclovir after hematopoietic stem-cell transplantation: impact on herpes simplex virus (HSV) disease and drug-resistant HSV disease. J Infect Dis 196(2):266–70 22. Fatahzadeh M, Schwartz RA (2007 Nov) Human herpes simplex virus infections: epidemiology, pathogenesis, symptomatology, diagnosis, and management. J Am Acad Dermatol 57(5):737–63 23. Ferrari A, Luppi M, Potenza L et al (2005 Nov) Herpes simplex virus pneumonia during standard induction chemotherapy for acute leukemia: case report and review of literature. Leukemia 19(11):2019–21 24. Frangoul H, Wills M, Crossno C et al (2007 Dec) Acyclovirresistant herpes simplex virus pneumonia post-unrelated stem cell transplantation: a word of caution. Pediatr Trans­ plant 11(8):942–4 25. Gasparetto EL, Escuissato DL, Inoue C et  al (2005 May) Herpes simplex virus type 2 pneumonia after bone marrow transplantation: high-resolution CT findings in 3 patients. J Thorac Imaging 20(2):71–3 26. Gilbert C, Bestman-Smith J, Boivin G (2002 Apr) Resistance of herpesviruses to antiviral drugs: clinical impacts and molecular mechanisms. Drug Resist Updat 5(2):88–114 27. Graham BS, Snell JD Jr (1983 Nov) Herpes simplex virus infection of the adult lower respiratory tract. Medicine (Baltimore) 62(6):384–93 28. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients; recommendations of the CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2000;6: 659–734 29. Hann IM, Prentice HG, Blacklock HA et al (1983) Acyclovir prophylaxis against herpes virus infections in severely immunocompromised patients: Randomised double blind trial. Br Med J (Clin Res Ed) 287:384–388 30. Hirsch MS (1995) Herpes simplex virus. In: Mandell GL, Bennett JE, Dolan R (eds) Principles and practice of ­infectious diseases. Churchill Livingstone, New York, pp 1336–1345 31. Jensen WA, Rose RM, Hammer SM et al (1986) Pulmonary complications of orthotopic liver transplantation. Trans­ plantation 42:484–490 32. Keating MJ, Flinn I, Jain V et al (2002) Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 99:3554–3561 33. Kim EA, Lee KS, Primack SL et al (2002) Viral pneumonias in adults: radiologic and pathologic findings. Radiographics Oct;22 Spec No:S137–S49 34. Kingreen D, Nitsche A, Beyer J et al (1997) Herpes simplex infection of the jejunum occurring in the early post-transplantation period. Bone Marrow Transplant 20:989–91

24  Herpes Simplex Virus Pneumonia in Patients with Hematologic Malignancies 35. Kitabayashi A, Hirokawa M, Horiuchi T et  al (2000 Jan) Late-onset herpes simplex virus-associated interstitial pneumonia after allogeneic bone marrow transplantation. Bone Marrow Transplant 25(2):225–6 36. Klainer AS, Oud L, Randazzo J et al (1994 Jul) Herpes simplex virus involvement of the lower respiratory tract follo­ wing surgery. Chest 106(1 Suppl):8S–14S, discussion 34S-35S 37. Kleymann G (2003) Novel agents and strategies to treat herpes simplex virus infections. Expert Opin 12:165–83 38. Koelle DM, Corey L (2008) Herpes simplex: insights on pathogenesis and possible vaccines. Annu Rev Med 59:381–95 39. Liebau P, Kuse E, Winkler M et  al (1996 Mar–Apr) Management of herpes simplex virus type 1 pneumonia following liver transplantation. Infection 24(2):130–5 40. Ljungman P, Ellis MN, Hackman RC et  al (1990 Jul) Acyclovir-resistant herpes simplex virus causing pneumonia after marrow transplantation. J Infect Dis 162(1):244–8 41. Ljungman P (2002 Jul) Prevention and treatment of viral infections in stem cell transplant recipients. Br J Haematol 118(1):44–57, Review 42. Ljungman P (2004) Viral infections: current diagnosis and treatment. Hematol J 5(Suppl 3):S63–8 43. Machado CM, Vilas Boas LS, Dulley FL et al (1997 Mar) Herpes Simplex Virus Shedding in Bone Marrow Transplant Recipients During Low-Dose Oral Acyclovir Prohylaxis. Braz J Infect Dis 1(1):27–30 44. Mettenleiter TC, Klupp BG, Granzow H (2006) Herpesvirus assembly: a tale of two membranes. Curr Opin Microbiol 9(4):423–9 45. Meyers JD, Flournoy N, Thomas ED (1980) Infection with herpes simplex virus and cell-mediated immunity after marrow transplant. J Infect Dis 142:338–346 46. Meyers JD, Flournoy N, Thomas ED (1982 Nov–Dec) Nonbacterial pneumonia after allogeneic marrow transplantation: a review of ten years’ experience. Rev Infect Dis 4(6):1119–32 47. Mintz L, Drew WL, Hoo R et al (1980 May) Age-dependent resistance of human alveolar macrophages to herpes simplex virus. Infect Immun 28(2):417–20 48. Miyazato A, Kishimoto H, Tamaki K et  al (2001 Aug) Herpes simplex virus bronchopneumonia in a non-immunocompromized individual. Intern Med 40(8):836–40 49. Morfin F, Bilger K, Boucher A et al (2004 Aug) HSV excretion after bone marrow transplantation: a 4-year survey. J Clin Virol 30(4):341–5 50. Nadelman CM, Newcomer VD (2000) Herpes simplex virus infections. New treatment approaches make early diagnosis even more important. Postgrad Med 107:189–2000 51. Nash G, Foley FD (1970 Dec) Herpetic infection of the ­middle and lower respiratory tract. Am J Clin Pathol 54(6):857–63 52. Nash G (1972 Jun) Necrotizing tracheobronchitis and bronchopneumonia consistent with herpetic infection. Hum Pathol 3(2):283–91 53. Orlowski RZ, Mills SR, Hartley EE et al (2004 Nov) Oral valacyclovir as prophylaxis against herpes simplex virus reactivation during high dose chemotherapy for leukemia. Leuk Lymphoma 45(11):2215–9 54. Prellner T, Flamholc L, Haidl S et al (1992) Herpes simplex virus–the most frequently isolated pathogen in the lungs of

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Pneumocystis Pneumonia in Non-AIDS Immunocompromised Patients

25

Élie Azoulay, Virginie Lemiale, Achille Kouatchet, François Vincent, Antoine Roux, Guillaume Bollée, and Patricia Roux

Contents 25.1 Introduction........................................................... 313 25.2 Transmission.......................................................... 314 25.3 Patients at Risk for PCP....................................... 314 25.3.1 Hematological Malignancies.................................. 314 25.4 Immunosuppressive Drugs and Risk of PCP.................................................................... 315

25.10 Curative Treatment of PCP.................................. 322 25.10.1 Antimicrobial Therapy............................................ 322 25.10.2 Adjuvant Steroids.................................................... 322 25.11 Prophylaxis of Pneumocystis pneumonia............. 323 25.11.1 Antimicrobial Drugs Available............................... 323 25.11.2 Indications for Prophylaxis..................................... 323 25.12 Conclusion............................................................. 323 References............................................................................ 323

25.5 CD4+ Lymphocyte Counts in H ­ IV-Negative Patients Developing PCP...................................... 315 25.6 Differences in Physiopathology Between Patients with and Without AIDS......................... 316 25.7 Clinical and Radiological Presentation of PCP in HIV-Negative Patients......................... 316 25.7.1 Clinical Presentation............................................... 316 25.7.2 Radiological Presentation....................................... 316 25.8 Diagnostic Strategy............................................... 316 25.8.1 Respiratory Samples Collecting Techniques.......... 316 25.8.2 Laboratory Diagnosis.............................................. 318 25.9 Prognosis of PCP in HIV-Negative Patients....... 321 25.9.1 Mortality................................................................. 321 25.9.2 Prognostic Factors................................................... 322

É. Azoulay (*), V. Lemiale, A. Roux, and G. Bollée Service de Réanimation Médicale, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010, Paris, France and Medical Intensive Care Units, Saint-Louis Hospital, Paris 7 University, Paris, France e-mail: [email protected] F. Vincent University, Avicenne Hospital, Paris 13 University A. Kouatchet Angers University Hospital P. Roux Parasitology-Mycology Department, Saint-Antoine Hospital, Paris 6 University, Paris, France

25.1 Introduction Pneumocystis pneumonia (PCP) remains one of the leading causes of morbidity and mortality among AIDS patients all over the world [1–3]. However, PCP is also a life-threatening opportunistic infection that can occur in other immunocompromised patients, mainly in solid organ transplant recipients, patients with cancer disease, hematological malignancy and those treated for autoimmune or inflammatory diseases [1–3]. PCP is caused by Pneumocystis jirovecii, a pathogen first identified in the early twentieth century by Chagas and subsequently by Carinii in rat lungs. These authors believed wrongly that they had found a new form of trypanosome. However, several years later, it was established that it was an original species, called Pneumocystis carinii. For many decades, pneumocystis was classified as a protozoan, until new phylogenetic studies demonstrated that it was related to the fungi [4]. Pneumocystis organisms have been identified in several mammalians, but in fact, different pneumocystis species with distinct genetic characteristics exist, with each species being host-specific. Thus, the pneumocystis infecting humans was named Pneumocystis jirovecii [3].

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_25, © Springer-Verlag Berlin Heidelberg 2011

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É. Azoulay et al.

Over the last years, advances in hematological treatments (including new drugs, high dose and intensive chemotherapy with bone marrow or stem cell transplantation) and immunomodulation resulted in an increased number of patients with impaired immunity and risk for PCP. This review focuses on practical aspects relevant to risk factors, diagnosis and treatment of PCP, in order to provide to clinicians an actual clinical picture of PCP in non-AIDS patients.

25.2 Transmission PCP was long thought to result from reactivation of latent infection acquired during childhood. This theory was supported by the seroprevalence of antiPneumocystis antibodies at a young age, the high rate of PCP among infants with AIDS, the presence of Pneumocystis jirovecii in respiratory specimens from patients without immunosuppression and without clinical signs of PCP, and by the characteristics of the organism itself, consistent with long-term carriage [5]. However, several lines of evidence subsequently ruled out the possibility of reactivation of latent infection as the sole mechanism for PCP and found that infection more likely results from environmental exposure or person-to-person transmission [5–7]. In this way, it was shown that Pneumocystis DNA was present in the environment, including pond water and various air samples, and that PCP incidence was increased in certain ­geographic areas. Additional data suggest that Pneumocystis jirovecii acquisition could result in a number of cases from airborne transmission from asymptomatic carriers or from patients with PCP [5, 6, 8]. Nevertheless, isolation of patients with PCP is not currently recommended or applied [5].

25.3 Patients at Risk for PCP Several retrospective studies have led to identification of clinical conditions associated with the occurrence of PCP in HIV-negative immunocompromised patients (Tables 25.1 and 25.2). Fifty years ago, PCP cases were reported in prematurely born and malnourished infants [9]. Nowadays, in rich countries, patients who are the most likely to develop PCP are those suffering from hematological malignancy, solid cancer, inflammatory or autoimmune disease, and solid organ transplant recipients [10–13]. Among those treated for hematological malignancies, five group of patients are at higher risk for PCP [14–16], namely, (1) patients with lymphoproliferative disorders such as lymphoma or acute lymphocytic leukemia (ALL); (2) patients receiving high doses or long-term steroids; (3) recipients of allogeneic but also autologous bone marrow or stem cell transplants; (4) patients treated using anti-CD20 [17] or anti-CD52 antibodies; and (5) patients with deep and prolonged lymphocytopenia after chemotherapy, such as fludarabin. Awareness of patients at risk for PCP is of great importance for clinicians who have to identify the patients requiring prophylaxis and cases where diagnosis of PCP must be considered.

25.3.1 Hematological Malignancies It has long been established that children with acute lymphoblastic leukemia receiving chemotherapy have a high risk of PCP. In a study by Hugues et al., the attack rate reached 4.1% in this population [18]. Subsequently, PCP cases were reported in almost all hematological malignancies [14, 15]. Although the exact incidence

Table 25.1  Underlying conditions in four series of non-AIDS patients with PCP Zahar [49] Yale [20] n = 39 (%) n = 116 (%)

Roblot [48] n = 130 (%)

Bollée [48] n = 56 (%)

Hematological malignancies

28 (71.8)

35 (30.2)

75 (57.7)

44 (78.6)

Solid tumors

7 (17.9)

15 (12.9)

18 (13.8)

9 (16.1)

Solid organ transplantation

0

29 (25)

9 (6.9)

0

Inflammatory diseases

0

26 (22.4)

27 (20.8)

0

Miscellaneous

4 (10.3)

11 (9.5)

1 (0.8)

3 (5.4)

25  Pneumocystis Pneumonia in Non-AIDS Immunocompromised Patients Table 25.2  Incidence of PCP in various types of malignancies (Adapted from [11]) PCP cases Patients Rates (%) Lymphomas

34

9,907

0.34

Acute lymphocytic leukemia

5

2,929

0.17

Other leukemia

16

5,023

0.32

Solid tumors

30

26,085

0.11

Cerebral tumors

21

3,098

0.68

Bone marrow transplantation

22

1,348

1.63

rate of PCP for each group of hematological malignancies is unknown, the highest incidence seems to occur in lymphoid leukemia and non-Hodgkin’s lymphoma, with attack rates being around 0.2–0.5% [11, 14]. Cancer patients who develop PCP have often received chemotherapy. However, in our experience, PCP may also be inaugural of the underlying disease, occurring before any immunosuppressive therapy [16]. Patients undergoing autologous or especially allogeneic hematopoietic stem cell transplantation (HSCT) are also likely to develop PCP. Although older studies showed that PCP occurred in most cases within the first 6 months after allogeneic HSCT, this notion was ruled out by more recent reports. In a recent retrospective study, PCP occurred at a median of 14.5 months after allogeneic HSCT, with the attack rate being 2.5% [19]. Moreover, in most cases, patients were receiving immunosuppressive therapy for chronic graft-versushost disease or had a relapse of their hematological malignancy [19].

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­ IV-negative patients showed that 90.5% were curH rently receiving steroids when PCP occurred. Median daily dose and median duration of steroids were equivalent to 30 mg and 12 weeks, respectively, and 25% of patients had received as little as 16 mg of pred­nisone daily [20]. However, patients not taking corticosteroids may also develop PCP. Indeed, in a recent retrospective study by our group of 56 HIV-negative patients with PCP, we observed that 24 patients (42.8%) were not receiving steroids when PCP occurred [16]. This is a crucial issue emphasizing that clinicians have to consider the possibility of PCP occurrence also in patients not receiving corticosteroids. Risk of PCP in cancer patients has been shown to be associated with the intensity of chemotherapy [18]. The precise role of a particular cytotoxic drug in PCP occurrence is often difficult to establish due to the association of several drugs in most patients. Certain drugs, such as fludarabine, cladribine, cyclophosphamide or methotrexate, have been suspected to be associated with a particularly high risk of PCP; however, these data remain elusive [1, 2, 21, 22]. Among immunosuppressive therapies used after solid organ transplantation, anti-lymphocytes antibodies clearly increase the risk of PCP [23]. PCP risk associated with azathioprine and cyclosporine therapy appears low, whereas it seems higher with tacrolimus [24]. Uncertainties persist regarding the risk associated with mycophenolate-mofenil and sirolimus use. Despite ancecdotal reports, actual risk of PCP related to newer drugs, such as anti-TNFa or anti-CD52 antibodies, has not yet been established.

25.4 Immunosuppressive Drugs and Risk of PCP

25.5 CD4+ Lymphocyte Counts in ­HIV-Negative Patients Developing PCP

In HIV-negative patients developing PCP, the immunocompromised state is partly linked to factors related to the underlying disease causing specific immunosuppression, but is also a consequence of treatments such as steroids, cytotoxic drugs and other immunomodulative drugs. Regardless of the associated underlying disease, steroids have largely been pointed out as a major ­predisposing factor for PCP in HIV-negative patients. A retrospective analysis of 116 cases of PCP in

PCP has been largely described in HIV-infected patients with a circulating CD4+ T lymphocyte count lower than 200/mm [3]. In other immunocompromised patients, the CD4+ count has also been shown to be related to the risk of PCP. PCP seems more likely to occur in patients with a CD4+ count lower than 300/ mm [3]. This suggests that CD4+ counts could be of value to detect patients at risk for PCP and determine those who should receive prophylaxis against PCP. However, the real value of CD4+ count monitoring in

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HIV-negative patients remains to be established. The total lymphocyte number should be taken into account.

25.6 Differences in Physiopathology Between Patients with and without AIDS In a study by Limper et  al., bronchoalveolar lavage (BAL) analysis of patients with PCP revealed important differences between patients with and without AIDS. Compared with AIDS patients, each of the other immunocompromised categories (hematological malignancies, solid cancers, solid organs transplantations and steroids therapy) had significantly lower organism numbers and more inflammation, estimated by neutrophil count. Furthermore, inflammation in BAL was inversely correlated with oxygenation and survival [10]. These data explain, at least partly, the differences observed in the clinical presentation of PCP between patients with and without AIDS. Along this line, in HIV infected patients, we previously reported the independent relationship between BAL neutrophilia and severity (hypoxemia) and outcomes (mortality) [25]. This may in part explain how HIVinfected patients with PCP have lower mortality rates compared to non-HIV patients with PCP [26].

25.7 Clinical and Radiological Presentation of PCP in HIV-Negative Patients

É. Azoulay et al.

clinical presentation is typically severe, with rapidly evolving bilateral lung involvement and marked hypoxemia. By comparison with AIDS patients, PCP presents as a more acute and severe disease among HIV negative patients, causing acute respiratory failure and often need for mechanical ventilation [16, 28, 29].

25.7.2 Radiological Presentation Radiographic features of PCP are similar in patients with and without AIDS [29]. Typically, bilateral or less frequently unilateral interstitial infiltrates are observed (Figs.  25.1–25.3). Rarely, chest radiography may be normal at an early stage. Also, atypical presentations may be misleading (Fig.  25.4). Only few data are ­specific to non-AIDS patients. Findings from high-­ resolution CT scans (HRCT) are available to date. A pattern of extensive ground-glass attenuation, which is often distributed in a patchy fashion, with predilection for perihilar regions of the lungs, is the most common feature (Figs. 25.1–25.4). In addition to the infiltrates, atypical HRCT features, such as nodules, nodular components or cavities, may be seen. The presence of these atypical images may be related to granuloma formation in response to PCP (Fig.  25.4), but are more often indicative of a concomitant cancer or infectious disease processes affecting the lungs. Conversely to AIDS patients, cysts related to PCP have not been described in HIV-negative patients with PCP.

25.8 Diagnostic Strategy

25.7.1  Clinical Presentation

25.8.1 Respiratory Samples Collecting Techniques

HIV-negative patients with PCP typically present with fever in about 60–90% of cases, dyspnea in 75–95% and cough in 50–80%. Although in some cases the evolution is more insidious, fever and respiratory symptoms develop over weeks [16]. Delay from onset of symptoms to diagnosis is rather short, varying from 1 to 14 days in most cases. Clinical examination commonly reveals tachypnea and diffuse crackles at lung auscultation. PaO2 in room air is usually strongly decreased, around 50–70 mmHg [14–16, 27]. Thus,

Owing to the lack of specificity of clinical and radiological presentation, diagnosis of PCP requires microbiological examination from a relevant sample to identify Pneumocystis jirovecii. Differences in organism number between patients with and without AIDS have to be borne in mind to address the issue of an adequate diagnostic procedure in non-AIDS immunocompromised patients. Several procedures are available for obtaining respiratory samples. Induced sputum (IS), a technique

25  Pneumocystis Pneumonia in Non-AIDS Immunocompromised Patients

317

a

b

Fig. 25.2  Hypoxemia in a 31-year-old ALL patient treated by long-term steroids. Chest X Ray (panel a) and High resolution CT scan (panel b) were suggestive of pneumocystis pneumonia. Giemsa staining on BAL fluid analysis was positive Fig.  25.1  Acute respiratory failure in a chronic lymphocytic leukemia (CLL) patients treated by cyclophosphamide, fludarabine and rituximab. Observance of prophylaxis was hazardous. Induced sputum performed before any antibiotics revealed cystic forms of Pneumocystis jirovecii

consisting of collection of a sputum specimen by a respiratory therapist after inhalation of nebulized saline for 20 min, has been proven to be a useful technique for the diagnosis of PCP. Bronchospasm may complicate the technique. Also, failure to collect this specimen in hypoxemic patients can be related to non-tolerance of the saline nebulization. Because of concerns about spreading tuberculosis during the procedure, this procedure is not indicated for patients suspected of having TB. Whereas the sensitivity of direct examination on IS from AIDS patients is up

to 90% in certain centers, [4] the few available data concerning HIV-negative patients suggest a lower sensitivity of around 50% [30]. Combining a rigorous technique for collecting the sputa and having it done by a trained mycologist clearly make it more sensitive. Bronchoscopy with bronchoalveolar lavage (BAL) represent a more efficient technique for diagnosing PCP [31]. Once again, the sensitivity of direct examination in HIV-negative patients is not well defined, but appears lower than in AIDS patients, around 60–70% [32]. The timing between antibiotic administration and induced sputum or BAL sampling is a key issue. BAL examination samples can be sent to several laboratories, increasing the diagnostic yield. Therefore, concomitant bacterial, viral or

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a

b

Fig. 25.4  Atypical presentation of Pneumocystis pneumonia in a 68-year-old patient with refractory T lymphoma receiving a third-line chemotherapy and anti-CD52 antibodies

Fig. 25.3  Acute respiratory failure 15 months after allogeneic stem cell transplantation for AML. Prophylaxis was withdrawn at 1 year. Chest X Ray (panel a) and High resolution CT scan (panel b) were suggestive of pneumocystis pneumonia. Induced sputum and BAL were negative for pneumocystis. A positive pneumocystis PCR raised concerns about the negative BAL. Re-examination (on a ­rescue smear) of BAL revealed trophic forms of pneumocystis

fungal infections can be diagnosed. However, this can also be done using a noninvasive diagnostic strategy [30]. An important limitation of the BAL procedure is the risk of aggravating the respiratory state and the need for mechanical ventilation, which are associated with a high mortality rate [33]. Interestingly, a concomitant pulmonary infection due to viruses, especially cytomegalovirus, bacteria or fungi, is frequently detected by BAL in patients with PCP (Fig. 25.7b) [10]. However, no comparative strategy

has demonstrated the benefit of performing BAL, which remains the procedure to perform when IS has failed to identify pneumocystis, concerning mortality or morbidity. Rarely, when less invasive procedures have failed to detect PCP, surgical lung biopsy should be considered [14]. However, the use of polymerase chain reaction (PCR) has made surgical biopsy no longer indicated for PCP patients.

25.8.2 Laboratory Diagnosis A major obstacle to studying and detecting pneumocystis is the impossibility of culturing this organism, despite many attempts [1, 2].

25  Pneumocystis Pneumonia in Non-AIDS Immunocompromised Patients

25.8.2.1 Direct Examination

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a

At first, the detection of Pneumocystis jirovecii in  respiratory samples depends on direct examination, which is based on tinctorial stains and immunofluorescence. Several staining methods, such as calcofluor white, Gomori-Grocott or toluidine blue, only allow detection of cysts, and also mark other fungi (Figs. 25.5a and 25.6) [34]. Other stains, such as Wright–Giemsa (Fig.  25.5b), Diff-Quik and Gram-Weigert, can detect both intracystic bodies (spores) and cysts and trophic forms, but their interpretation may be difficult as they also color other organisms. The development of indirect

a

b

b Fig. 25.6  Pneumocystis jirovecii cysts in BAL fluid. TBO staining (×1,000, panel a). Pneumocystis jirovecii cysts in induced sputum. Musto staining (×1,000, panel b)

immunofluorescence using monoclonal antibodies was a significant advance, providing a method that is rapid and more sensitive than conventional stains for detecting Pneumocystis jirovecii in respiratory samples (Fig. 25.7a) [35].

25.8.2.2 Polymerase Chain Reaction as a Significant Advance for Diagnosing PCP Fig. 25.5  Direct examination of BAL fluid (×1,000, panel a). Cluster of Pneumocystis jirovecii. Cluster of Pneumocystis jirovecii in BAL fluid (Giemsa staining, panel b)

The detection of Pneumocystis jirovecii in clinical specimens was greatly improved by the use of

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a

on IS [32, 37]. However, since HIV patients have numerous cysts or trophic forms of pneumocystis, the usefulness of PCR remains controversial. The question about the interpretation of a positive PCR deciding between infection and colonization is often raised. In a study by Sing et al., the PCR value was investigated in different immunocompromised groups. For combined BAL and IS specimens, sensitivity and specificity were respectively calculated to 80% and 100% in AIDS patients, 86% and 97% in transplant recipients, 100% and 95% in cancer patients, and 100% and 98% in other immunocompromised patients [32]. In another study, Pneumocystis jirovecii was not detected by direct examination of BAL in 7 of 37 HIVnegative immunocompromised patients with PCP, and PCR was the only microbiological indication of Pneumocystis jirovecii in these patients [37]. These data emphasize that routine microbiological evaluation for PCP must involve the use of PCR in all respiratory samples from HIV-negative immunocompromised patients. Nevertheless, this excessively sensitive technique may overestimate PCP diagnosis in patients who are only colonized. In an evaluation by our study group in 448 non-HIV patients, the negative predictive value of pneumocystis PCR was almost 100% [38]. This allows clinicians to rule out the clinical diagnosis of PCP based on the results of PCR, even on induced sputa and without performing BAL. Additional evaluation is warranted. This needs to include (1) actual risk factors for PCP, (2) the level of clinical suspicion of PCP and (3) the results of quantitative PCR, which seem likely to make the difference between colonization and infection.

b

25.8.2.3 PCR and Colonization Fig. 25.7  Pneumocystis jirovecii cysts in BAL fluid (immunofluorescence, panel a). Giemsa staining in induced sputum revealing infection by pneumocystis, Cryptococcus neoformans and colonization by Candida albicans (×1,000, panel b)

polymerase chain reactions (PCR). In 1990, Wakefield et al. developed a new technique for DNA amplification specific to pneumocystis using primer sequences for the mitochondrial 5S rRNA gene of P. carinii [36]. Subsequent studies highlighted the efficiency of this technique. Principally in AIDS patients, sensitivity was evaluated at 80–100% and 70–85% on BAL and IS specimens, respectively. Specificity appeared also excellent, around 80–100% on BAL and 90–95%

However, a benefit of the PCR technique is the excellent sensitivity allowing the detection of a very low pneumocystis burden related to colonization in asympto­matic patients. Although lung colonization by Pneumocystis jirovecii was also reported in immunocompetents patients with various bronchopulmonary diseases [39], immunocompromised patients appear much more likely to be asymptomatic pneumocystis carriers [40]. Longterm steroid use and low CD4+ counts [41] have been shown to be associated with higher colonization rates. In a study by Leigh et al., ISs obtained in 10 immunocompetent patients and 20 solid organ transplant recipients, all asymptomatic, were screened for Pneumocystis jirovecii using PCR and immunofluorescence. All 30 specimens were negative for Pneumocystis jirovecii

25  Pneumocystis Pneumonia in Non-AIDS Immunocompromised Patients

using immunofluorescence, and 5 transplant patients but no immunocompetent patients were positive for Pneumocystis jirovecii ­according to PCR alone. One of these patients developed PCP 6 weeks after sputum induction [42]. However, the risk of clinical PCP occurrence in an asymptomatic patient with colonization remains largely uncertain to date. Thus, PCR positivity alone on a respiratory sample may reflect true infection, but also colonization.

25.8.2.4 Real-Time Quantitative PCR Larsen et al. developed a rapid, sensitive and quantitative Touchdown-PCR (TD-PCR) assay, which constituted another significant improvement in diagnosing PCP and resolved, at least partly, the problem of distinction between true infection and colonization [43]. In a blind retrospective study of respiratory samples obtained in HIV-negative immunocompromised patients, the concentration of pneumocystis DNA measured by using quantitative TD-PCR was significantly higher in patients with PCP than in those with other respiratory disorders. Moreover, application of a cutoff value allowed distinguishing between infection and colonization. Real-time PCR has been demonstrated to be the best technique that avoids contamination, allows quantitation of the fungus copy number and can discriminate between infection and colonization [44]. PCR performed on IS represents an alternative to BAL that may be effective and non-invasive. An oral wash collected after the patient gargles and rinses the mouth with sterile saline appears to be a highly desirable diagnostic specimen, as it can be obtained easily and quickly in a number of patients, including in those unable to sustain invasive procedures. Oral washes do not contain enough organisms to be detected by direct microscopic examination, but PCR may detect pneumocystis DNA in such specimens. Moreover, Larsen et al. demonstrated that quantitative TD-PCR could be used for distinguishing between colonization and infection in oral washes, as in BAL specimens [43]. PCR on oral washes has also been shown to be a useful technique for diagnosing PCP in HIV-negative immunocompromised patients. Helweg-Larsen reported 100% sensitivity and specificity of TD-PCR on 26 oral washes collected in patients with hematological malignancies, with 8 having PCP [45]. Thus, examination of oral washes by TD-PCR is a promising technique to diagnose PCP and should be carried out in increasing numbers of centers for use in the near future.

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25.8.2.5 S-Adenosylmethionine Plasmatic Concentration Dosage Pneumocystis is the only cell known to be unable to synthesize S-adenosylmethionine, a key intermediary metabolite for all cells. Thus, pneumocystis must extract this compound from its host, resulting in the depletion of the infected animal. It was assessed that plasma S-adenosylmethionine was decreased in AIDS patients with PCP, and rapidly increased after recovery [46], suggesting that measurement of plasma S-adenosylmethionine could be of great value for diagnosing PCP. However, these promising results will have to be confirmed in the future before being put into use.

25.8.2.6 (1–3)-b-d-Glucan (1–3)-b-d-Glucan (BG) is present in the cell wall of most medically important fungi (except Cryptoccoccus sp. and zygomycetes sp.). In pneumocystis they are localized to the electron-lucent band under the cell membrane of the cysts. Recently, colorimetric assays have been developed (15) to detect BG. The Fungitell test© (Associates of Cape Cod, Inc., Cape Cod, MA) is a chromogenic kinetic test (approved in 2003 by the US Food and Drug Administration) for the presumptive diagnosis of invasive fungal infections. Studies showed that high BG sera levels >500 pg/mL are found during pneumocystosis; [47] they noted that 29/30 confirmed PCP cases were BG positive, and most of them were >500 pg/mL. The median value for the PCP-positive group was in excess of 500 pg/mL. The BG assay is a noninvasive serological test useful for the diagnosis of PCP.

25.9 Prognosis of PCP in HIV-Negative Patients 25.9.1 Mortality Prognosis of PCP is clearly worse in HIV-negative than in AIDS patients, with the mortality rate reported to be around 30–40%. Mortality is even higher in patients requiring mechanical ventilation, reaching 60–75% [14–16, 48].

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25.9.2 Prognostic Factors Many factors associated with mortality in HIV-negative patients with PCP have been described. Unsurprisingly, high respiratory and pulse rates, hypoxemia, involvement of four lung lobes, need for mechanical ventilation or vasopressors, high C reactive protein and lactate dehydrogenase levels, severity scores according to the Simplified Acute Physiology Score II or Organ System Failure score, and concomitant pulmonary infection have been associated with higher mortality [14, 16, 27, 48]. Receiving cancer chemotherapy [27, 49] and longterm steroids [14, 49] is also related to the occurrence of death. Interestingly, high neutrophil counts in BAL specimens are associated with more severe hypoxemia and higher mortality [10, 49], which may support the hypothesis of a beneficial effect of adjuvant high-dose steroids for non-AIDS patients, as previously reported for AIDS patients [50, 51].

É. Azoulay et al.

with other antimicrobial molecules is not recommended for treating PCP. In case of intolerance to TMP-SMX, pentamidine should be used as an alternative choice. Pentamidine can be administrated intravenously or by aerosol in mild forms of PCP. The most common adverse drug reaction to pentamidine is renal toxicity, which usually occurs after 2 weeks of treatment and can be prevented by adequate hydration. Other adverse effects, including hypotension (especially in case of rapid infusion), heart arrhythmias, hypo- or hyperglycemia, hypercalcemia, hyperkaliemia, pancreatitis and metallic taste may also occur. Atovaquone, dapsone and clindamycin-primaquine represent other options in the treatment of mild PCP in AIDS patients. However, due to the lack of data, these drugs cannot be recommended for current use in HIV-negative patients with PCP.

25.10.2 Adjuvant Steroids 25.10 Curative Treatment of PCP 25.10.1 Antimicrobial Therapy Medications used to treat PCP do not differ between patients with and without AIDS. As the most effective treatment, trimethoprim-sulfamethoxazole (TMP-SMX) given orally or intravenously for 3 weeks must be used as the first-line treatment unless contraindicated. TMPSMX acts by interfering with folate metabolism: TMP and SMX respectively inhibit dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS), which are two integral enzymes of folate synthesis. Emergence of mutations in the DHPS gene related to prophylaxis use has been a concern for several years. However, whether these mutations confer resistance to TMP-SMX remains largely uncertain and controversial. Adverse effects, including fever, rash, cytopenia, hyperkaliemia, hyponatremia, hepatitis and interstitial nephritis, occur less commonly (around 15%) in HIV-negative compared to AIDS patients [52]. The adjunction of folinic acid may lower the risk of neutropenia, but increases the risk for therapeutic failure. Due to the lack of synergy and the risk of occurrence of adverse effects, association

Steroids are recommended in AIDS patients with PCP who have severe hypoxemia (PaO2 under 70 mmHg on room air). Indeed, adjuvant steroids have been shown to result in a significant survival improvement by reducing the risk of respiratory failure and mortality [51]. Regarding HIV-negative patients, only a few retrospective studies, including a small number of patients, have investigated the effect of adjuvant steroids. In a study by Delclaux et  al., adjuvant steroids were not found to influence the mechanical ventilation requirements and mortality rate [53]. In another study by Pareja et al., adjuvant steroids were associated with a shorter duration of mechanical ventilation, oxygen therapy and stay in the ICU, without decreasing mortality [54]. In our recent study of 56 HIV-negative patients with PCP, we observed a trend toward decreased mortality in patients receiving adjuvant steroids (18.2% vs 42.2%, NS) [16]. Thus, a clear benefit from adjuvant steroids in HIV-negative patients with PCP has not been proved to date. However, considering the results and the limits of these studies, and on the basis of our personal experience, we believe that adjuvant steroids should be advised in HIV-negative patients with severe PCP.

25  Pneumocystis Pneumonia in Non-AIDS Immunocompromised Patients

25.11 Prophylaxis of Pneumocystis pneumonia 25.11.1 Antimicrobial Drugs Available Thirty years ago, TMP-SMX was demonstrated to be highly effective and well tolerated in the prevention of PCP among cancer patients [2, 18, 52]. Nowadays, TMP-SMX given orally remains the gold standard for PCP prophylaxis, similarly to curative treatment. Aerosolized pentamidine repeated every month might be an alternative for patients not tolerating TMP-SMX. Although this prophylactic regimen was demonstrated to be less effective than TMP-SMX, aerosolized pentamidine was associated with an increased risk of PCP and other infections, and a higher mortality in bone marrow transplant recipients. Dapsone is another available drug for preventing PCP. Dapsone inhibits DHPS as SMX. However, dapsone alone or associated with pyrimethamine is inferior to TMP-SMX. Moreover, TMP-SMX intolerance often predicts dapsone intolerance. Thus, it is not recommended to replace TMPSMX by dapsone in case of intolerance [55]. Finally, atovaquone constitutes an effective and well-tolerated alternate choice, also in bone marrow transplant recipients.

25.11.2 Indications for Prophylaxis Conversely to AIDS patients, no consensus has been reached concerning the indications for prophylaxis against PCP in HIV-negative patients. From our own experience and in view of the risk factors for PCP occurrence, we believe that patients who should receive prophylaxis are: • Patients with any immunological disorder, including cancer, hematological disease, autoimmune or inflammatory disorders, who are given more than 15 mg of prednisone daily (or the equivalent) for more than 4 weeks. • Patients with acute leukemia or non-Hodgkin’s lymphoma not in remission or receiving chemotherapy. • Patients undergoing allogenic HSCT; prophylaxis should be maintained for at least 1 year and maintained in patients receiving immunosuppressive

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drugs, and in those with relapse of their hematological malignancy or with longstanding GVHD. • Patients undergoing autologous HSCT, for at least 6 months; duration should be extended in patients receiving additional immunosuppressive drugs. • Solid organ transplant recipients should receive prophylaxis for 6 months after transplantation, except lung transplant recipients, who should have lifelong prophylaxis. TMP-SMX should be stopped during neutropenia and in patients receiving methotrexate. It remains unclear whether CD4+ monitoring should be used for detecting patients who require prophylaxis. However, a CD4+ count lower than 300/mm [3] should lead to prescribing prophylaxis, especially for patients with malignancies.

25.12 Conclusion In summary, PCP is a severe opportunistic infection, which may complicate the course of a wide variety of diseases leading to immunosuppression. For clinicians caring for immunocompromised patients, knowledge of conditions associated with PCP is crucial for identifying who should receive prophylaxis and suspecting PCP in order to implement an early, adequate diagnostic and therapeutic strategy. Long-term steroid use is an important but not the only risk factor for PCP patients. In the era of more intensive treatment regimens, new molecules used as cancer chemotherapy or immunomodulation, and extended survival of cancer patients suggest that clinicians need to maintain a high level of suspicion regarding PCP. The development of PCR and noninvasive methods, such as oral washes and b-1–3 glucan detection, constitutes important advances for diagnosing PCP, which should be available in an increased number of centers to allow optimal management of these patients.

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Diagnosis of Invasive Pulmonary Aspergillosis in Patients with Hematologic Diseases

26

Marie-Elisabeth Bougnoux, Fanny Lanternier, Emilie Catherinot, Felipe Suarez, and Olivier Lortholary

Contents 26.1 Risk Factors for Invasive Aspergillosis in Hematology Patients........................................... 327 26.2 Clinical Features..................................................... 328 26.3 Chest Computed Tomography Scan..................... 328 26.4 Laboratory Diagnosis............................................. 329 26.4.1 Mycological Microscopy and Culture...................... 329 26.4.2 Histopathology.......................................................... 330 26.4.3 Detection of Circulating Surrogate Markers............. 330 References............................................................................ 333

M.-E. Bougnoux (*) Unité de Parasitologie-Mycologie, Service de Microbiologie, Université Paris-Descartes. Hôpital Necker Enfants-Malades, 149, rue de Sèvres, 75015, Paris, France e-mail: [email protected] F. Lanternier Université Paris-Descartes. Hôpital Necker Enfants-Malades, Service de Maladies Infectieuses et Tropicales, Centre d’Infectiologie Necker-Pasteur, 149, rue de Sèvres, 75015, Paris, France

Invasive pulmonary aspergillosis (IPA) is a common infectious complication and a major cause of severe morbidity and mortality in patients with hematologic diseases. It is the leading cause of invasive fungal infections in hematopoietic stem cell transplant (HSCT) patients, accounting for 43% of invasive fungal infections [30]. Despite the availability of new antifungal agents, mortality rates range from 29% to 42% [26, 36, 50]. Several factors, including the severity of immunodeficiency secondary to underlying disease and its treatment, contribute to this extremely poor outcome [13, 16, 48, 67]. However, timely and accurate diagnosis is also of crucial importance for the prognosis [38, 74]. Establishing a definitive diagnosis of IPA remains difficult, and up to 30% of cases are unrecognized antemortem [17]. A substantial delay in establishing an early and accurate diagnosis remains a major impediment to the successful treatment of IPA. Because IPA is the leading cause of infectious deaths in patients with hematologic malignancies and has non-specific clinical presentation, optimized diagnostic procedures are necessary. Here, we will detail the different steps of the diagnosis of IPA in patients with hematologic diseases, focusing on the contribution of new diagnostic tools.

E. Catherinot and F. Suarez Service d’Hématologie, Université Paris-Descartes. Hôpital Necker Enfants-Malades, Paris, France

26.1 Risk Factors for Invasive Aspergillosis in Hematology Patients

O. Lortholary Service de Maladies Infectieuses et Tropicales, Centre d’Infectiologie Necker-Pasteur, 149, rue de Sèvres, 75015, Paris, France and Institut Pasteur, Unité de Mycologie Moléculaire, Centre National de Référence Mycologie et Antifongiques, CNRS URA3012, Paris, France

Recognition of patients at risk for invasive aspergillosis (IA) is crucial to undertake early active diagnostic procedures. The main defects in host defenses strongly associated with an increased risk for IPA are (1) prolonged

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_26, © Springer-Verlag Berlin Heidelberg 2011

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neutropenia, (2) qualitative defects in phagocyte function, and (3) deficit in cell-mediated immunity [18, 54, 58, 59]. Absolute neutrophil count <100/mm3 and a duration >10 days of neutropenia are major risk factors for IPA. Hematology patients at high risk of IPA include those with prolonged profound neutropenia, i.e., patients receiving cytotoxic chemotherapy for acute leukemia and patients with myelodysplastic syndrome (MSD), and recipients of HSCT. Patients with acute myeloid leukemia (AML) are more frequently affected, with a 10% incidence during post-induction or consolidation neutropenia [49, 51, 54]. Among intensively treated non-allografted patients, those with multiple myeloma are also at high risk of IPA [35]. Increased susceptibility of these patients probably results from the high dose of steroids they received. Finally, ambulatory patients with heavily treated lymphoid malignancies have now emerged as a major subgroup at high risk of invasive aspergillosis among hematology patients [36]. Incidence distribution of IPA is bimodal among allogeneic HSCT recipients. Allogeneic recipients are at increased risk for IPA during the preengraftment phase, when neutropenia is the prevailing risk factor. However, they also experience a second, postengraftment period of vulnerability coincident with the severe cell-mediated immunodeficiency resulting from graftversus-host disease (GVHD) [23, 41] and its treatment [23, 41]. IPA occurs in 5–15% of allogeneic HSCT, with a higher incidence in recipients of transplants with higher risks for GVHD, i.e., unrelated donor, mismatched transplant, and haploidentical [52]. The incidence of IPA is higher than 10% in patients who benefit from recently discovered procedures such as cord blood transplantation [48]. Of note, a decline in preengraftment aspergillosis has been observed due in part to the reduction of periods of neutropenia and to better measures for minimizing exposure to fungal spores [41, 61]. Nowadays, the majority of IPA occurs after engraftment, and GVHD has emerged as the predominant risk factor [20, 36, 61]. The genetic host factor may modulate the individual risk of IA. Indeed, among allogeneic HSCT recipients from unrelated donors, the donor TLR4 haplotype S4 is associated with an increased risk of invasive aspergillosis [7]. Mannose-binding lectin deficiency is also likely associated with aspergillosis [32].

M.-E. Bougnoux et al.

26.2 Clinical Features Invasive aspergillosis is mostly confined to the lungs, but sinusitis and central nervous system involvement can also occur [28]. In a recent multicenter study in France among 393 adults, IA was restricted to the lungs in almost 90% of the cases [36]. Fever that persists despite the administration of broad-spectrum antibiotics is suggestive of IPA. Respiratory symptoms and signs may be absent in neutropenic hosts. As the disease progresses, symptoms appear, cough and dyspnea being the most common. Pleuritic chest pain and hemoptysis are less frequent, but suggest pulmonary infarction and the tendency of Aspergillus spp. to invade blood vessels. In patients at high risk, these signs and symptoms, although not specific, are suggestive of IPA and drive for appropriate (active diagnostic) investigations, including detailed radiological and mycological evaluation.

26.3 Chest Computed Tomography Scan High-resolution CT scan is the gold standard imaging technique in IPA [10]. It should be done early when the diagnosis is suspected. Single or multiple nodules are the most common finding in early IPA in neutropenic and HSCT recipients. The “halo sign,” which is a mass-like infiltrate surrounded by groundglass opacity, is considered an early and transient sign of IPA (Fig.  26.1a). It reflects hemorrhages or edema around the nodule and is a characteristic chest CT feature of the angioinvasive organisms. In a recent study reviewing 235 patients with IPA, 94% of them had at least one macro-nodular lesion, and 61% had a halo sign [22]. Other CT aspects include consolidations, infarct-shaped nodules, cavitation and air-crescent sign. The air-crescent sign, defined as a crescentic pocket of gas surmounting a sequestrum within a nodule, indicates central necrosis of a nodular lesion, and it usually occurs late in the course of the disease at the time of neutrophil recovery (Fig. 26.1b). Of note, patients with suggestive signs, such as halo and air-crescent signs, have a better prognosis [22].

26  Diagnosis of Invasive Pulmonary Aspergillosis in Patients with Hematologic Diseases

a

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b

Fig. 26.1  CT scan appearance of invasive pulmonary aspergillosis in a 35-year-old patient undergoing chemotherapy for acute myeloid leukemia secondary to myelodysplasia. (a) Peripheral

nodular consolidation and halo sign (arrow). (b) Ten-day evolution after recovery from neutropenia, showing cavitation with air crescent sign

26.4 Laboratory Diagnosis

mycology laboratories. They include (1) wet mount examination of the sample after addition of chlorazol black, a chitin stain that aids in the visualization of the hyphal elements, and (2) staining with Grocott-Gomori silver and Giemsa stain of the microscope slides prepared from touch preparation of the biopsy specimen, or from cytospin of fluid samples. Fluorescent dyes, such as Calcofluor® white, which selectively binds polysaccharides within fungal cell walls, improve direct examination of the specimens. Aspergillus spp. typically appears as slender, septate hyphae that exhibit angular dichotomous branching. Sensitivity of direct microscopy is approximately 30% for sputum samples, 50% for BAL fluid, 70% for CT-guided lung biopsy, and 90% for open-lung biopsy [29, 74]. Detection of fungal elements can provide a presumptive diagnosis in less than 1 h; its diagnostic value depends of the origin of the sample. Visualization of fungal elements morphologically compatible with Aspergillus spp. in a lung biopsy allows definite diagnosis of invasive fungal infection (IFI), but does not prove IPA. In BAL samples, their presence has a higher predictive value for the diagnosis than in sputum samples. In a recent multicenter study in France, direct examination was performed in 325/393 (83%) patients with the lowest rate in the acute leukemia group (95/135 = 70%). The global yield of direct examination was 56% (182/325), with a significantly lower rate in the allo-HSCT group [36].

Clinical and radiological IPA presentation is similar to other mold/dimorphic (zygomycosis or endemic mycosis) and bacterial infections (tuberculosis, Pseudomonas aeruginosa). Therefore, microbiological diagnosis is of primary importance. If noninvasive tests are negative, bronchoscopy with bronchoalveolar lavage (BAL) or CT-guided needle biopsy should be performed when possible [33].

26.4.1 Mycological Microscopy and Culture Respiratory specimens, including sputum, fluid obtained by endotracheal aspiration or BAL, as well as lung biopsies, i.e., CT-guided lung biopsy and openlung biopsy, should be obtained for microscopy and fungal culture.

26.4.1.1  Direct Microscopy Direct microscopic examination has to be performed for all clinical respiratory samples and biopsies. Several procedures are currently being used by

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26.4.1.2  Fungal Culture Isolation of Aspergillus strain by culture of fluid and tissue specimens is essential in IPA because it (1) confirms microscopic findings and the diagnostic of IPA, (2) allows an accurate identification of Aspergillus species and testing of the antifungal susceptibility of the strain. Cultures are best performed on Sabouraud dextrose agar with the addition of antibiotic agents at both 30°C and 35°C. The growth is visible after between 48 h to several days, depending on the fungal load in the analyzed specimen and on the Aspergillus species involved. In a recent multicenter study, samples processed for mycological culture were available in 324/393 (82%) patients. When performed, culture was positive for 76% (245/324), from 53% (50/95) for acute leukemia and 68% (45/66) for AlloHSCT to >86% for the other groups [36].

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identification, and the use of molecular identification is strongly recommended to obtain accurate species identification. Molecular identification of Aspergillus species is based on the partial sequencing of genes coding for beta-tubulin, calmodulin, or actin [5]. This approach has been included in recent guidelines [46, 76].

26.4.1.4  Antifungal Susceptibility Testing Antifungal drug resistance of some Aspergillus spp. is now well established [53, 62, 68, 71]. Some of the newly described species responsible for IPA have decreased susceptibility to antifungal drugs. Therefore, the determination of the in  vitro susceptibility of the strains is necessary. However, there is no formal recommendation for the method to use.

26.4.1.3  Identification of Aspergillus spp. The choice of appropriate antifungal therapy is strongly influenced by the inherent resistance phenotype of each Aspergillus species, and correct identification is therefore of paramount clinical importance [46, 75]. Current identification of the species of Aspergillus is based on macroscopic and microscopic morphological characteristics, such as color, shape, ornamentation, and recognition of asexual or sexual stages. Sometimes conventional phenotypic methods are not sufficient to provide accurate identification, and molecular identification is used as second-line for species identification. Aspergillus fumigatus is the leading etiological agent of IPA followed by Aspergillus flavus, Aspergillus niger, Aspergillus terreus, and Aspergillus nidulans [75]. When positive (245/324 – 75.6%), cultures mainly yielded A. fumigatus (84%) in a recent French study [36]. For these common species, a conventional approach routinely provides an adequate level of identification. For the new species of Aspergillus spp. recently reported as responsible for cases of IPA, such as Aspergillus lentulus, Neosartorya fischeri [34], N. pseudofischeri [66], N. hiratsukae [24], N. udagawae [72], A. insuetus [21], A. calidoustus [55, 70], or A. niveus [3], phenotypic methods do not allow a correct

26.4.2 Histopathology Different patterns of tissue injury can be observed in the lung tissues of hematology patients with IPA. In patients with profound neutropenia, but also in HSCT recipients, histopathologic patterns are characterized by angioinvasion, defined by the presence of hyphal structure within the wall or lumen of arteries or veins, and intra-alveolar hemorrhage. In non-neutropenic patients, histopathologic patterns characterized by inflammatory necrosis and granulomas are more prevalent [64].

26.4.3 Detection of Circulating Surrogate Markers Biologic markers, including fungal antigens or DNA released by the Aspergillus hyphae during growth in host tissues, are used as early indicators of disease. Their diagnostic value has been evaluated in adult and pediatric hematological patients. Standardized assays allowing detection of galactomannan and b-1–3-dglucan antigens are now included in the EORTC/MSG criteria for the diagnosis of IA [15]. As of today, molecular methods for detection of Aspergillus DNA

26  Diagnosis of Invasive Pulmonary Aspergillosis in Patients with Hematologic Diseases

in clinical specimens are not included, because the techniques have not been standardized yet.

26.4.3.1 Detection of Galactomannan Antigen Galactomannan (GM) is a polysaccharide cell wall component of Aspergillus species released in blood by fungal hyphae during growth in tissues in IA. The commercially available sandwich enzymelinked immunosorbent assay (ELISA) (Platelia® Aspergillus, BioRad, Marnes-La-coquette, France) detects approximately 1 ng/mL GM [69]. GM detection can be performed in different biologic specimens, including serum, BAL fluids, CSF, and urine. However, the assay has only been formally evaluated in BAL and serum.

Serum Aspergillus GM Detection The usefulness of the GM detection for diagnosis of IA has been clearly demonstrated both in adult and pediatric patients with hematologic disorders [39, 63]. The threshold for positivity when the assay is performed in serum is an index of >0.5 [40]. Screening for circulating GM twice weekly during high-risk susceptibility periods in hematology patients (patients with prolonged neutropenia after chemotherapy or HSCT, and patients receiving high doses of corticosteroid) reduces the time to diagnosis of IPA [9, 39]. Sensitivity, specificity, and positive and negative predictive values of GM for IA were 88.2%, 95.8%, 75%, and 98.3 %, respectively, in high-risk adult hematology patients [65]. However, the reported predictive values of the GM detection have been highly variable, depending on the population, i.e., pediatric or adult, non-neutropenic hematology patients, and prevalence of IA related to the type of hematology disorders in the tested patients [12, 43]. In the recent French study, galactomannan tests were more often positive (>68%) for acute leukemia and AlloHSCT than for the others (<42%) [36]. Major Causes of Variable Test Performances High Variations of GM Levels in Serum Conditions   The Aspergillus species involved and the neutrophil counts modify the serum GM levels and therefore the

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performance of GM detection for IPA [12, 25]. GM levels have been reported to be lower in non-neutropenic hematology patients than in patients with profound neutropenia (<100 PMN/mm3) [12]. Higher GM levels in neutropenic patients could reflect a higher Aspergillus burden because of more extensive lesions. Indeed, in an autopsy study, histological patterns were different between non-neutropenic HSCT recipients and neutropenic patients, the latter having a higher Aspergillus burden and more angio-invasive lesions but less inflammation [11]. Last, GM levels may be higher in patients with angioinvasive aspergillosis than in those with airway IA [27]. False-Positive Detection Several causes of false-positivity of the GM Platelia ELISA have been reported, including cross reactivity with several non-Aspergillus molds [14], presence of GM-like material in fluids for intravenous hydratation, such as plasmalyte, solutions for parenteral nutrition, or some antibiotic agents, such as piperacillin/tazobactam [4, 73] and more recently saccharose containing therapeutic immunoglobulins [8]. In addition, high rates of false positivity have also been reported in allogeneic HSCT recipients during the first 100 days after transplantation or in those with gastrointestinal GVHD [1, 2]. Passage of dietary GM through injured mucosa is the favored hypothesis of false positivity in these patients. GM as a Marker of Aspergillosis Outcome The outcome of patients with IA appears strongly correlated with the serum GM index. Indeed, persistent GM index positivity is associated with failure and death, whereas normalization of the GM index is associated with survival in neutropenic patients and in non-neutropenic onco-hematology adult patients [47, 77].

BAL Aspergillus GM Detection GM assay performed in BAL fluids is a valuable adjunctive diagnostic tool to other conventional microbiological tests, i.e., mycological examination and culture [19, 56]. A recent study in neutropenic and non-neutropenic hematology patients found that BAL

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GM testing performed better than conventional methods for the microbiological diagnosis of IA in hematology patients when an index cutoff of >1 was used [37]. GM detection in BAL had a sensitivity of 57.6% (95% CI, 40.8–72.8%) and a specificity of 95.6% (95% CI, 87.8–98.5%) in a recent study performed in St. Louis Hospital in Paris [6].

26.4.3.2 Detection of Beta-1-3-D-Glucan Antigen Beta-1-3-d-glucan antigen (BG) is a fungal cell wall component circulating in the blood of patients with invasive fungal infections (IFI), i.e., IA, invasive candidiasis, Pneumocystis pneumonia, and other invasive fungal diseases. However, its detection does not differentiate among the various fungal etiologic agents. The assay has been recently included in the EORTC/ MSG criteria for the diagnosis of IFI [15]. Two commercial kits are available (Fungitec G-test® and Fungitell®). Several causes of false-positivity have been reported, including intravenous immunoglobulin or albumin use, and hemodialysis with cellulose membrane [31]. False-positive results have also been reported in bacteremic patients and in those treated with fungus-derived antibiotics such as amoxicillin– clavulanic acid [44, 45, 57]. Therefore, the BG assay must be used and interpreted cautiously in such patients. Although a recent study has reported the usefulness of BG monitoring for early diagnosis of IFI in patients with acute leukemia, studies in larger groups of hematology patients are still needed to define the place of this test in the diagnosis strategy of IPA [60].

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about an optimal methodology [76]. Nevertheless, DNA detection should be quickly validated. Indeed, it appeared from the result of a recent large metaanalysis that a single PCR-negative result is ­sufficient to exclude a diagnosis of proven or probable IA [42]. In addition, the excellent performances of weekly PCR screening of circulating DNA on large serum volumes in high-risk patients with hematological malignancies have also been clearly demonstrated [65]. The European Organization for Research and Treatment of Cancer/Mycosis study group (EORTC/ MSG) has published criteria to define possible, probable, and proven fungal infections [15]. Criteria for IPA, which are summarized in Tables  26.1 and 26.2, can help to undertake active diagnostic procedures in patients with a high suspicion index. Diagnosing IPA relys on the association of compatible host factors and clinical presentation combined with non-invasive diagnostic tests. Whereas galactomanann antigen use is well established, b-d-glucan suffers from a lack of specificity and PCR from a lack of standardization. When these tests cannot lead to a diagnosis of probable aspergillosis, invasive procedures such as BAL and/or CT-guided needle biopsy should be undertaken to confirm diagnosis, even though those patients are often cytopenic. However, diagnostic procedures should not delay antifungal treatment as soon as IPA is suspected.

Table 26.1  Criteria required for proven, probable, or possible invasive pulmonary aspergillosis (Adapted from [15]) IPA Criteria Proven

26.4.3.3  DNA Detection by PCR Screening for circulating DNA of Aspergillus spp. by PCR has shown potential in the definitive diagnosis of IA [42]. However, a major concern is the lack of standardization of the PCR procedures. Marked differences are observed between studies in the type of the samples tested (whole blood vs serum), the volume of sample to analyze (large vs small), the DNA extraction procedures, and the targets used for amplification. Currently, no consensus has been reached

Histopathologic, cytopathologic, or direct microscopic examination of a specimen obtained by needle aspiration or biopsy in which hyphae forms are seen accompanied by evidence of associated tissue damage Isolation of Aspergillus strain by culture of a specimen obtained by needle aspiration or biopsy, excluding bronchoalveolar lavage fluid

Probable

A host factor, a clinical criterion, and a mycological criteriona

Possible

A host factor and a clinical criteriona

See Table 26.2

a

26  Diagnosis of Invasive Pulmonary Aspergillosis in Patients with Hematologic Diseases Table 26.2  Host factors, clinical and mycological criteria for invasive pulmonary aspergillosis in patients with hematological disorders (Adapted from [15]) Type of Criteria criteria Host factors

Recent history of neutropenia (<0.5 × 109 neutrophils/L (<500 neutrophils/mm3) for >10 days) temporally related to the onset of fungal disease Receipt of an allogeneic stem cell transplant Prolonged use of corticosteroids at a mean minimum dose of 0.3 mg kg−1 day−1 of prednisone equivalent for >3 weeks Treatment with other recognized T cell immunosuppressants, such as cyclosporine, TNF-a blockers, specific monoclonal antibodies (such as alemtuzumab), or nucleoside analogues during the past 90 days Inherited severe immunodeficiency (such as chronic granulomatous disease or severe combined immunodeficiency)

Clinical

Presence of one of the following three signs on CT: Dense, well-circumscribed lesions(s) with or without a halo sign, air-crescent sign, cavity

Mycological  irect test D (cytology, direct microscopy, or culture)

Presence of fungal elements morphologically compatible with Aspergillus spp. in BAL, sputum, bronchial brush, and/ or isolation of Aspergillus strain in these respiratory specimens

Indirect tests

Galactomannan antigen detected in plasma, serum, bronchoalveolar lavage fluid, or CSF b-d-glucan detected in serum

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Emerging Fungal Infections

27

Marcia Garnica and Marcio Nucci

Contents 27.1 Introduction............................................................. 337 27.2 The Host................................................................... 338 27.3 The Fungi................................................................. 339 27.4 Clinical Manifestation............................................ 339 27.5 Radiology................................................................. 341 27.6 Other Diagnostic Tools........................................... 343 27.7 Treatment................................................................ 344 27.8 Conclusions.............................................................. 345 References............................................................................ 345

M. Garnica and M. Nucci (*) Department of Internal Medicine, Hematology Unit and Mycology Laboratory, University Hospital, Universidade Federal do Rio de Janeiro. Rua Professor Rodolpho Paulo Rocco, 255 Sala 4A, 12 21941-913, Rio de Janeiro, Brazil e-mail: [email protected]

27.1 Introduction Invasive fungal disease (IFD) represents a major complication in patients with cancer, especially patients with hematological malignancies, and hematopoietic stem cell transplant (HCT) recipients [69]. While Aspergillus species remain the most frequent agent of IFD, other fungi have emerged, including Fusarium spp., Zygomycetes, the agents of phaeohyphomycosis [37, 63], and non-fumigatus Aspergillus spp. [31]. The term emerging infection (Table 27.1) may be used to denote an infection that has newly appeared in the population, is rapidly increasing in incidence or geographic range, a new clinical presentation of an infection caused by a known pathogen or even a new antifungal susceptibility pattern of a known pathogen [43]. These infections are a major challenge for clinicians because they frequently carry a poor prognosis as a consequence of various factors: clinicians may not be aware of that clinical presentation or the new pathogen, and this may result in a delay in establishing the diagnosis; a good laboratory is mandatory to appropriately identify the agent and to perform antifungal susceptibility tests; the emerging pathogens are usually resistant to various antifungal drugs; and these emerging infections are more likely to occur in severely immunosuppressed patients. In this chapter we will discuss the epidemiology, clinical presentation, radiology, diagnostic tools and treatment options for pulmonary infections caused by these emerging fungal pathogens in patients with hematological diseases. The following agents will be discussed: non-fumigatus Aspergillus, Fusarium spp., Zygomycetes, and the agents of phaeohyphomycosis.

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_27, © Springer-Verlag Berlin Heidelberg 2011

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338 Table 27.1  Definition of emerging fungal infections Emerging fungal infectionsa Non-fumigatus Aspergillus spp. Fusarium spp. Zygomycetes The agents of phaeohyphomycosis The term emerging infection may be used to denote an infection that has newly appeared in the population, is rapidly increasing in incidence or geographic range, a new clinical presentation of an infection caused by a known pathogen, or even a new antifungal susceptibility pattern of a known pathogen [43] a

27.2 The Host Host factors are probably the most important determinants of the emergence of fungal infections caused by unusual pathogens. These emerging fungi are usually nonpathogenic in the normal host (and even in less severely immunosuppressed patients), but emerge in patients with severe immunosuppression. Immunocompromised patients at high risk for IFD are those with prolonged neutropenia and/or severe T-cell immunodeficiency. Several chemotherapeutic agents impair T-cell defenses and hence may increase the risk of IFD. These include the purine analogs fludarabine, cladribine and deoxycorfomycin, and monoclonal antibodies alemtuzumab, infliximab and daclizumab [1, 8, 22, 23, 34, 35]. Indeed, cases of IFD have been increasingly reported in patients with lymphoproliferative diseases treated with some of these agents [24, 60, 62]. In addition to the use of specific immunosuppressive agents, changes in treatment strategies resulting in cumulative immunosuppression have also resulted in the emergence of IFD. This is the case of multiple myeloma in which the treatment evolved from the classical regimen of oral melphalan and prednisone, with minimal impact on the immune system, to strategies that include one or two autologous HCTs, high-dose corticosteroids, bortezomib and others [41]. In the context of HCT, practices that increase the risk and severity of graft versus host disease (GVHD) have a potential to increase the risk for IFD [54, 68]. These include: peripheral blood instead of bone marrow as the source of stem cells, increasing upper age limit, transplants with HLA-mismatched or unrelated donors, non-myeloablative transplants, and the use of donor lymphocyte infusions. In addition, patients submitted to multiple transplants and those receiving

M. Garnica and M. Nucci

transplants with T-cell depletion are at increased risk for these infections, probably because the immune reconstitution in such transplants is delayed [10]. The association of severe GVHD and mold ­infections is due to the combination of the immunodeficiency of GVHD itself, associated with the ­immunodeficiency caused by its treatment, and the reactivation of immunomodulatory viruses, such as cytomegalovirus. Severe GVHD requires the use of high-dose corticosteroids and, if refractory, other immunosuppressive agents that per se may increase the risk for mold infections. For example, in a study, the use of infliximab (an antitumor necrosis factor alpha) for the treatment of severe or refractory acute GVHD was associated with a higher risk for mold infections (aspergillosis and zygomycosis) by multivariate analysis [33]. Non-myeloablative transplants are associated with a higher frequency of mold infections [16, 21]. In a retrospective single-center study, mold infections occurred in 25 out of 163 patients submitted to nonmyeloablative transplants (four due to Zygomycetes and one due to Fusarium sp.). Risk factors for these infections by multivariate analysis included severe acute GVHD, chronic extensive GVHD and cytomegalovirus disease [12]. Risk factors for infection caused by Fusarium and Zygomycetes in HCT recipients have been assessed in a single-center retrospective study [32]. Underlying multiple myeloma and mismatched or unrelated transplants were associated with fusariosis (hazard ratios of 6.9 and 2.7, respectively), whereas underlying myelodysplastic syndrome (hazard ratio 4.1) and acute GVHD (hazard ratio 3.1) were predictors of zygomycosis. As pointed out, treatment of myeloma is associated with a cumulative and severe T-cell-mediated immunodeficiency [41]. The time of occurrence of the emerging fungal infections varies according to the agent. While scedosporiosis is more likely to occur before engraftment (during neutropenia), infection by Zygomycetes occurs later (>day + 90 after transplantation) in the setting of GVHD and its treatment [32]. By contrast, fusariosis has a trimodal distribution following HCT, with the first peak at a median of 16 days posttransplantation, a second peak between day + 61 and day + 80 (median day + 64), and a third peak after day + 360. A remarkable finding in the cases of late fusariosis is that they occurred in the context of chronic GVHD and no patient was neutropenic [44].

27  Emerging Fungal Infections

27.3 The Fungi Most of the emerging fungal pathogens are common soil saprophytes, and the main mechanism of acquisition is the inhalation of conidia, with subsequent pneumonia and/or sinusitis in a process similar to that of invasive aspergillosis. Nevertheless, some of these infections occur as a result of penetrating trauma (phaeohyphomycosis, fusariosis) or at sites of skin breakdown (fusariosis). While Aspergillus fumigatus is by far the most frequent species causing invasive aspergillosis, in recent years, the incidence of infection due to non-fumigatus species has also increased [31]. In a series of 40 cases of aspergillosis in patients with cancer from 1998 to 2001, 70% were caused by non-fumigatus Aspergillus. Among the 28 non-fumigatus Aspergillus spp., Aspergillus flavus was identified in 13 cases, Aspergillus terreus in 11, Aspergillus niger in 3, and Aspergillus nidulans in 1 case [59]. Aspergillus terreus is an important emerging agent of aspergillosis [15]. The reasons for the emergence of this species in particular are not clear, but may be related to local epidemiologic characteristics (including the environment and patient populations), since its incidence varies among different institutions: A. ­terreus was responsible for 30% of cases of invasive aspergillosis at a center in Vienna, Austria [25], 1% of 1,477 cultures positive for Aspergillus spp. from 24 US centers in a 1-year period [48], and 7% of cases of invasive aspergillosis enrolled in a large worldwide clinical trial [17]. Aspergillus ustus is frequently found in foods, soil and indoor environments, and has been increasingly reported as cause of invasive disease, mostly in severely immunosuppressed patients [46, 53, 61]. Breakthrough infection in patients receiving voriconazole and caspofungin has been reported [19, 47, 56]. Infections caused by a recently recognized species of Aspergillus have been reported [4, 5]. The organism, which, according to classical morphological typing methods, is typically identified as A. fumigatus, clusters as a unique species with multilocus sequence typing [4], supporting the proposed designation of Aspergillus lentulus. Fusarium is a plant pathogen and a soil saprophyte that causes a broad spectrum of infections in humans, including superficial, locally invasive and disseminated infection. The most frequent species causing

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infection in humans are Fusarium solani, Fusarium oxysporum and Fusarium moniliforme [36, 39]. Fusariosis emerged as an important and frequently fatal infection in immunosuppressed patients, the majority of cases occurring in patients with acute leukemia developing prolonged and profound neutropenia [42]. More recently, cases of fusariosis occurring in patients without neutropenia but with severe T-cell immunodeficiency have been reported, underscoring the importance of the immunity on the emergence of opportunistic fungal infections [44]. Zygomycetes is a class of filamentous fungi that is subdivided into two orders: Mucorales and Ento­ morphthorales. Most infections in humans are caused by the Mucorales. The spectrum infection caused by Zygomycetes ranges from cutaneous to disseminated disease, and the most frequent clinical form of the disease in neutropenic patients is pneumonia [13]. The genus Scedosporium contains two medically important species: Scedosporium apiospermum and Scedosporium prolificans. Scedosporium apiospermum has a sexual form called Pseudallesceria boydii. In immunocompromised patients, S. apiospermum causes deeply invasive infections such as pneumonia, sinusitis and brain abscess [7, 66], and most cases occur in the setting of severe neutropenia. Pulmonary involvement is common in HCT recipients: in a series of ten cases, nine had lung disease, frequently with sinusitis (six cases). Scedosporium prolificans causes disseminated infection in neutropenic patients [52]. Agents of phaeohyphomycosis have been increasingly reported as causes of systemic infection in immunocompromised patients. A report of infection at a cancer center from 1989 to 2008 showed that the incidence of phaeohyphomycosis increased in this period, from 1.0 to 3.1 cases per 100,000 patient-days. Lungs, skin (38% each) and sinuses (36%) were the most frequently involved organs.

27.4 Clinical Manifestation Lung involvement is frequent in most of the emerging fungal infections. While their clinical presentation may overlap, some features are characteristic of specific pathogens and may therefore be of help in establishing the correct diagnosis (Table 27.2). In addition,

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Table 27.2  Diagnostic characteristics of invasive pulmonary mold infections in neutropenic patients Aspergillosis Fusariosis Zygomycosis Scedosporiosis

Phaeohy­phomycosis

Similar to aspergillosis

Similar to aspergillosis; S. prolificans: metastatic skin lesions

Similar to aspergillosis

Similar to aspergillosis

Similar to aspergillosis, >10 nodules and pleural effusion more frequent

Similar to aspergillosis

Similar to aspergillosis

Negative

Positive (60%)

Negative

S. prolificans: positive (70%)

May be positive

Serum galactomannan

Sensitivity 70%; specificity 92%. Good at ruling out the diagnosis

Positive results reported in F. solani and F. oxysporum

Negative

Negative

Positive results reported with some species

Serum 1,3-betad-glucan

Positive

Positive

Negative

May be positive

May be positive

Clinical picture

Fever, cough, Similar to pleuritic chest pain aspergillosis + metastatic skin lesions (70%)

Radiologic pattern

Angioinvasion, nodules +/- halo sign

Blood culture

a major determinant of the clinical form of fungal pneumonia is the immune status of the host. One side of the spectrum is represented by patients with severe (<100/mm3) and prolonged (>15  days) neutropenia, mostly patients with acute leukemia receiving induction remission, and allogeneic HCT recipients in the early post-transplant period. In these patients, infection is characterized by angioinvasion, with intra-alveolar hemorrhage and pulmonary infarction. The second group is represented by non-neutropenic allogeneic HCT recipients. In these patients, pneumonia occurs in the context of severe T-cell immunodeficiency caused by GVHD and its treatment. Although angioinvasion may be observed, it is less frequent than in severely neutropenic patients. However, although the number of neutrophils is normal, there is a paucity of inflammatory cells in lung tissue, indicating that these patients are functionally neutropenic [58]. The most frequent clinical presentation of pneumonia caused by emerging molds in neutropenic patients is that of persistent or recurrent fever in patients with prolonged neutropenia, associated with signs of pulmonary infarction: dry cough and pleuritic chest pain. By contrast, in non-neutropenic allogeneic HCT recipients, the clinical manifestations are subtle and nonspecific. Fever is frequently absent. In a series of 84 patients with fusariosis and an underlying hematologic disease, lung infiltrates

(presumed to be due to fusariosis) were present in 54% of patients and, like in aspergillosis, consisted of nonspecific alveolar or interstitial infiltrates, nodules and cavities. The clinical presentation was non-specific, with some presenting with a clinical picture similar to invasive aspergillosis, with dry cough, pleuritic chest pain and shortness of breath [42]. Among 294 cases of fusariosis reported in the literature until 2002, lung involvement was present in 114 (39%) and was more common among immunocompromised (109 cases, 42%) than immunocompetent patients (5 cases, 16%; p = 0.004). Risk factors for fusarial pneumonia include a diagnosis of acute leukemia, prolonged neutropenia and HCT. Pneumonia as the sole manifestation of fusariosis was reported in 14  cases (11 in immunocompromised patients). The most frequent radiological pattern was alveolar infiltrates (46%), pulmonary nodules and interstitial infiltrates (9% each), and cavities (4%). Nodular and cavitary lesions were more common among patients with isolated lung involvement (6 of 14, 43% vs 18 of 100, 18%; p = 0.04). A confirmation of lung involvement was obtained in 60 cases (53%). The most frequent pulmonary material that contributed to the diagnosis was lung tissue obtained from autopsy (63%), followed by sputum (17%), bronchial aspirate (8%), lung biopsy (7%) and bronchoalveolar lavage (BAL 5%). Patients with fusarial pneumonia were

27  Emerging Fungal Infections

more likely to die compared to those without lung involvement (77% vs 59%, p < 0.001), even after controlling for status of the host defenses and neutropenia [40]. In another study, 61 cases of fusariosis in HCT recipients (including some previously reported cases) were identified in nine centers. Infection occurred in 54 allogeneic and 7 autologous HCT recipients. Similar to the other reports, the most frequent clinical picture was disseminated infection (75%), with positive blood cultures (43%) and/or metastatic skin lesions (54%). Other patterns of infection included pneumonia and sinusitis. Neutropenia was present in 46% of allogeneic and in 71% of autologous HSCT recipients, and neutropenic patients were more likely to have disseminated disease (p = 0.001). Acute and chronic GVHD was present in 57% and 20% of patients, respectively. A remarkable characteristic of invasive fusariosis that distinguishes it from aspergillosis is the high frequency of positive blood cultures and metastatic disseminated skin lesions (Fig.  27.1). This is because Fusarium spp. produces yeast-like structures (adventitious sporulation) that facilitate dissemination and growth in the blood. Patients with disseminated disease typically have multiple erythematous papular or nodular and painful lesions, frequently with central necrosis giving the lesions an echtyma gangrenosum-like appearance. Fusarial skin lesions involve practically any site, with predominance in the extremities, and evolve rapidly, usually over a few days (range 1–5 days). Lesions at different stages of evolution (papules, nodules and necrotic lesions) and concomitant myalgias

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(suggesting muscle involvement) are frequently present [39]. Some patients present cellulitis at the site of onychomycosis, local trauma or intertrigus. These lesions may be the primary site of disseminated infection. Pneumonia is the most frequent clinical presentation of zygomycosis in patients with hematological malignancies and in HCT recipients, as opposed to the typical rhinocerebral form that affects diabetic patients [2, 3, 20, 26–28, 55, 64, 65]. The clinical presentation is similar to that of invasive pulmonary aspergillosis, but the radiologic picture may differ (see below). Most cases develop as breakthrough infections if treatment with antifungal agents effective against Aspergillus spp. is administered [9]. In immunocompromised patients, S. apiospermum causes deeply invasive infections, such as pneumonia, sinusitis and brain abscess [7, 66]. The clinical presentation is similar to aspergillosis. Neutropenia and organ transplantation represent the most frequent underlying conditions. The most frequent clinical finding in sinopulmonary infection caused by Scedosporium spp. is fever, followed by dyspnea and pleuritic chest pain. By the time of diagnosis of Scedosporium pneumonia, signs of disseminated disease are usually present, including maculo-papular or nodular skin lesions, myalgias and focal neurologic signs. Similar to fusariosis, infection due to S. prolificans (but not S. apiospermum) is frequently associated with positive blood cultures and metastatic skin lesions [29]. In a review of 25 cases of scedosporiosis in cancer patients, 3 were HCT recipients. All had positive blood cultures and two had skin lesions [29]. In a review of 72 cases of disseminated phaeohyphomycosis, the most frequent agent was S prolificans, accounting for 30 cases. Five of these patients were HCT recipients, all with neutropenia [52].

27.5 Radiology

Fig.  27.1  Typical metastatic erythematous skin lesions in a patient with disseminated fusariosis

Computed tomography (CT) of the chest is an important diagnostic tool of pneumonia caused by the emerging fungal pathogens. The chest X-ray is not useful, especially if the patient is neutropenic. It is often abnormal, but the appearance is nonspecific, with patchy segmental or lobar consolidations [9]. The radiologic features in severely neutropenic patients reflect the angioinvasive nature of the disease.

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Nodular opacities, with or without a ground-glass opacity surrounding the nodule (halo sign), are the most typical lesions. They represent pulmonary edema and hemorrhage surrounding an area of coagulative necrosis. The halo sign is not specific to aspergillosis and has been described in pneumonia caused by other fungi, including Fusarium spp., Scedosporium spp. and Zygomycetes (Fig. 27.2). The halo sign may also be present in a variety of non-infectious (such as Wegener granulomatosis, Kaposi sarcoma and hemorrhagic metastases) and infectious conditions (such as viral pneumonias and tuberculosis). Other findings in the CT scan include nodules, consolidations, groundglass opacities, mass, air bronchogram, effusions and cavitation (Figs. 27.3–27.5). In non-neutropenic allogeneic HCT recipients, mold infections may be characterized by angioinvasion (like in neutropenic patients) or airway invasion. In the later form, the radiologic picture is that of a bronchopneumonia. The X-ray shows patchy air space consolidation, with or without small nodules (Fig. 27.6), and the CT scan exhibits air space consolidations or nodules. The radiologic manifestations of fusarial pneumonia are indistinguishable from those caused by Aspergillus spp., with alveolar infiltrates, pulmonary nodules, interstitial infiltrates and cavities [42, 44]. By contrast radiologic manifestations of Zygomycosis may differ. A study compared the radiologic aspects of

Fig. 27.2  Chest CT showing nodule with ground-glass opacity surrounding the nodule (halo sign) in a neutropenic patient with invasive fusariosis

M. Garnica and M. Nucci

pulmonary Zygomicosis and aspergillosis. Zygo­ mycosis was more likely to present with multiple (>10) nodules and pleural effusion [9]. Radiologic manifestations in phaeohyphomycosis were mostly pulmonary nodules, with or without halo sign and nonspecific pulmonary infiltrates. Pleural effusion and cavitary lesions seem to be less frequent [6].

Fig. 27.3  Chest CT showing ground-glass infiltrates and pleural effusion in a non-neutropenic hematopoietic stem cell transplant recipient with invasive fusariosis

Fig. 27.4  Chest CT showing alveolar infiltrates and nodule in a neutropenic patient with invasive fusariosis

27  Emerging Fungal Infections

Fig.  27.5  Chest CT showing nodule with cavity and groundglass opacity surrounding the nodule in a neutropenic patient with zygomycosis (Courtesy of Belinda P. Simões, University of São Paulo, Ribeirão Preto, Brazil)

Fig. 27.6  Chest X-ray showing bilateral patchy infiltrates in a neutropenic patient with invasive fusariosis

27.6 Other Diagnostic Tools The mainstay of the diagnosis of invasive fungal infections is the demonstration of tissue invasion by fungal elements and the growth of the organism from tissue culture. Unfortunately, in the majority of cases this is not achieved because clinical conditions preclude lung biopsy. Since the appearance of most hyaline and black molds is similar in tissue (hyalohyphomycosis and phaeohyphomycosis), culture of tissue is critical.

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Indeed, it is practically impossible to distinguish infection with Aspergillus spp. from infection by any of the angioinvasive molds such as Fusarium and Scedosporium spp., or the dematiaceous fungi such as Bipolaris, Exserohilum and Alternaria spp. and to a lesser extent infections caused by the agents of zygomycosis. For the diagnosis of phaeohyphomycosis, the Fontana-Masson stain for melanin is important and reveals the typical pigmentation of hyphae. Culture of respiratory secretions is an alternative, but the interpretation of fungal growth may be difficult. Fungi may colonize the airways, and many of the emerging fungal pathogens are frequent contaminants in the laboratory. The isolation of several colonies from the same specimen or the same fungus from different specimens is highly suggestive of a true growth, whereas the isolation of a single colony from only one biological sample should raise the question if it is a contamination. When interpreting the result of a mycological examination, a positive direct examination of the biological material in addition to isolation of the fungus in culture provides a more reliable diagnosis. However, the sensitivity of detection by smear examination is low. Therefore, the clinical significance of a single positive culture with a negative direct smear is difficult to determine. Potassium-hydroxide concentrated smears prepared from sedimented remains of clinical specimens may be useful to differentiate between contamination and infection [70]. In addition to culture-based diagnostics, serologic tests have been developed. The Bio-Rad Platelia™ sandwich ELISA for the detection of Aspergillus antigens in blood has good sensitivity for the early diagnosis of aspergillosis [50]. The test has excellent performance characteristics in profoundly neutropenic patients provided it is performed at least two or three times a week and supported by chest CT scan findings. Although considered specific for the diagnosis of aspergillosis, the test may be positive in infections caused by emerging pathogens, such as Fusarium solani, Fusarium oxysporum, Paecilomyces spp., Acremonium spp. and Alternaria spp. Limitations of the test include reduced sensitivity during receipt of  mold-active antifungal agents and false-positive results with the use of some semi-synthetic b-lactam antibiotics, including ampicillin, amoxicillin-clavulanate and piperacillin-tazobactam [51]. The galactomannan assay may also be performed in BAL fluid [30].

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Detection of 1,3-beta-d-glucan in the serum is another tool that has been developed for the early diagnosis of IFD. It can detect a much broader spectrum of fungal species than the Platelia™ sandwich ELISA, including Candida, Aspergillus, Fusarium and others [45]. False-positive readings may result from the use of albumin or immunoglobulins, exposure to glucancontaining gauze, hemodialysis and some antimicrobial preparations (amoxicillin-clavulanate).

27.7 Treatment As pointed out, the management of emerging fungal infections is challenging (Table 27.3). The first step is to make all efforts to perform the correct diagnosis, including isolation of the agent and its identification to species level. Antifungal susceptibility tests may be of help in selecting the appropriate antifungal agent, although a good correlation between minimal inhibitory concentration and clinical outcome has not been established. The typical antifungal susceptibility profile of Fusarium spp. is that of relative resistance to most antifungal agents. However, different species may have different patterns of susceptibility. F. solani and Fusarium verticillioides are usually resistant to azoles and exhibit higher MICs for amphotericin B than other Fusarium spp. [38]. By contrast, F. oxysporum, and F. moniliforme may be susceptible to voriconazole and posaconazole. The relevance of these in  vitro data is not clear, because there are not enough data documenting a correlation between MIC values and the clinical outcome. Because of the lack of clinical trials and the critical role of immune reconstitution in outcome of fusariosis, the optimal treatment strategy for patients with severe fusarial infection remains unclear. However, taking the results of in  vitro susceptibility tests, it seems more prudent to start treatment of systemic fusariosis with a lipid preparation of amphotericin B. The response rate to a lipid formulation of amphotericin B appeared superior to that of deoxycholate amphotericin B (46% vs 32%, respectively) in a series of 84 cases in patients with hematological malignancies [42]. Other options for the treatment are voriconazole and posaconazole [38]. The prognosis of invasive fusariosis has been poor regardless of the underlying disease. In a series of

M. Garnica and M. Nucci

84 patients with hematological malignancies and fusariosis, 33 of which were HCT recipients, only 21% of patients were alive 90 days after the diagnosis of fusariosis. Multivariate predictors of poor outcome were persistent neutropenia and the use of corticosteroids [42]. In HCT, the mortality rate was 89% among 61 cases reported in the literature and 87% in a series of patients from 9 centers [44]. In this later series, the actuarial survival at 90 days postdiagnosis of fusariosis was only 13%, with a median survival of 13 days after diagnosis. The single variable associated with poor outcome was persistent neutropenia. The clinical presentation of infection due to A. terreus is not different from aspergillosis caused by other species. The most important difference is in susceptibility to antifungal agents. MIC50 of voriconazole (0.25 mg/mL) and itraconazole (0.062 mg/mL) tested in 43 A. terreus isolates was not different from A. fumigatus (0.25 and 0.25  mg/mL, respectively. By contrast, MIC50 of amphotericin B was 2 mg/mL for A. terreus and 1 mg/mL for A. fumigatus [11]. Accordingly, a retrospective analysis of 83 cases of infection due to A. terreus showed higher mortality rates if patients received a preparation of amphotericin B compared to patients receiving voriconazole, and by multivariate analysis, the single variable significantly associated with better outcome was receipt of voriconazole [57]. A. terreus exhibits variable susceptibility to antifungal agents. In a report of six cases in HCT recipients, four out of six isolates exhibited MICs for amphotericin B of 2 mg/mL. MICs for voriconazole were also high (4  mg/mL in two isolates and 8  mg/mL in four isolates) [46]. S. apiospermum is susceptible to the antifungal triazoles, but not to amphotericin B, whereas S. prolificans is resistant to all antifungal agents [11]. In a series of eight pediatric patients with scedosporiosis, all six S. apiospermum infections responded to voriconazole, but not the two patients infected with S. prolificans [67]. In another study, response to voriconazole was also observed in two of six patients with S. apiospermum infection and in one of four with S. prolificans infection [49]. Zygomycosis usually has a very devastating clinical course, especially the rhinocerebral form. Therefore, early diagnosis is paramount. Indeed, the prognosis of such infections has improved in recent years because of improvements in early diagnosis [13]. Like in the other mycoses, the prognosis of infection is also

27  Emerging Fungal Infections

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Table 27.3  Therapeutic management in emerging fungal infections Fusariosis Aspergillus terreus Azoles

Voriconazole

Scedosporiosis

In vitro resistance for Fusarium solani and verticillioides Variable susceptibility Optimal first line therapy

F. oxysporum and F. moniliforme may be susceptible in vitro

S. apiospermum is sensitive, but S. prolificans is resistant

Acceptable alternative to polyenes

Optimal first line therapy

Posaconazole Lipid preparation of amphotericin B

Zygomycosisa

Posaconazole is a salvage therapy Increased MIC50 compared to Fumigatus (2 mg/mL)

Higher MICs for Fusarium Optimal first line solani and verticillioides therapy High doses are recommended Optimal first line therapy

S. apiospermum and S. prolificans are resistant

Combined medical and surgical treatment

a

influenced by the clinical form of disease, with a better prognosis for localized forms and death in most patients with disseminated infection [20]. Another aspect of zygomycosis is that a combined surgical and medical treatment seems to be crucial. A study showed cure or improvement occurred in 7 of 11 transplant recipients with zygomycosis who were treated with amphotericin B colloidal dispersion. All cured patients had been submitted to a surgical procedure in addition to antifungal treatment [18]. Amphotericin B is considered the drug of choice for the treatment of zygomycosis, and high doses are recommended [13]. In addition, posaconazole has been studied as salvage therapy with fair response rates [14, 42]. However, concerns regarding the use of posaconazole in the primary treatment of zygomycosis include its low in  vitro activity against some of the most frequent agents of zygomycosis and the lack of an intravenous formulation.

27.8 Conclusions The emergence of fungal pathogens is a consequence of the dynamic interaction between the host, the environment and the pathogen. Although some fungal infections seem to have emerged as a result of selective pressure of the widespread use of prophylactic antifungal agents, the large majority of fungal infections emerge because of severe immunosuppression.

Therefore, as the number and categories of immunosuppressed patients expand, it is not surprising that the list of emerging fungal infections is increasing. Clinicians must be aware of new pathogens, new clinical entities and clinical presentations in order to make a prompt and accurate diagnosis. Mycology laboratories must be prepared to establish the diagnosis to the species level, and this may require the availability of molecular tests. Finally, antifungal susceptibility tests should also be available to select the most adequate antifungal drug. Acknowledgment: Financial support: Pro Vita, Rio de Janeiro (M.G.) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil, Grant 200425/2009-9 (M.N.)

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346   5. Balajee SA, Weaver M, Imhof A, Gribskov J, Marr KA (2004) Aspergillus fumigatus variant with decreased susceptibility to multiple antifungals. Antimicrob Agents Chemother 48:1197–1203   6. Ben-Ami R, Lewis RE, Raad II, Kontoyiannis DP (2009) Phaeohyphomycosis in a tertiary care cancer center. Clin Infect Dis 48:1033–1041   7. Bouza E, Munoz P (2004) Invasive infections caused by Blastoschizomyces capitatus and Scedosporium spp. Clin Microbiol Infect 10(Suppl 1):76–85   8. Bulpa P, Dive A, Sibille Y (2007) Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease. Eur Respir J 30:782–800   9. Chamilos G, Marom EM, Lewis RE, Lionakis MS, Kontoyiannis DP (2005) Predictors of pulmonary zygomycosis versus invasive pulmonary aspergillosis in patients with cancer. Clin Infect Dis 41:60–66 10. Daly A, McAfee S, Dey B, Colby C, Schulte L, Yeap B, Sackstein R, Tarbell NJ, Sachs D, Sykes M, Spitzer TR (2003) Nonmyeloablative bone marrow transplantation: infectious complications in 65 recipients of HLA-identical and mismatched transplants. Biol Blood Marrow Transplant 9:373–382 11. Espinel-Ingroff A, Johnson E, Hockey H, Troke P (2008) Activities of voriconazole, itraconazole and amphotericin B in vitro against 590 moulds from 323 patients in the voriconazole Phase III clinical studies. J Antimicrob Chemother 61:616–620 12. Fukuda T, Boeckh M, Carter RA, Sandmaier BM, Maris MB, Maloney DG, Martin PJ, Storb RF, Marr KA (2003) Risks and outcomes of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplants after nonmyeloablative conditioning. Blood 102:827–833 13. Gonzalez CE, Rinaldi MG, Sugar AM (2002) Zygomycosis. Infect Dis Clin North Am 16:895–914, vi 14. Greenberg RN, Mullane K, van Burik JA, Raad I, Abzug MJ, Anstead G, Herbrecht R, Langston A, Marr KA, Schiller G, Schuster M, Wingard JR, Gonzalez CE, Revankar SG, Corcoran G, Kryscio RJ, Hare R (2006) Posaconazole as salvage therapy for zygomycosis. Antimicrob Agents Chemother 50:126–133 15. Hachem RY, Kontoyiannis DP, Boktour MR, Afif C, Cooksley C, Bodey GP, Chatzinikolaou I, Perego C, Kantarjian HM, Raad II (2004) Aspergillus terreus: an emerging amphotericin B-resistant opportunistic mold in patients with hematologic malignancies. Cancer 101: 1594–1600 16. Hagen EA, Stern H, Porter D, Duffy K, Foley K, Luger S, Schuster SJ, Stadtmauer EA, Schuster MG (2003) High rate of invasive fungal infections following nonmyeloablative allogeneic transplantation. Clin Infect Dis 36:9–15 17. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, Kern WV, Marr KA, Ribaud P, Lortholary O, Sylvester R, Rubin RH, Wingard JR, Stark P, Durand C, Caillot D, Thiel E, Chandrasekar PH, Hodges MR, Schlamm HT, Troke PF, de Pauw B (2002) Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 347:408–415 18. Herbrecht R, Letscher-Bru V, Bowden RA, Kusne S, Anaissie EJ, Graybill JR, Noskin GA, Oppenheim BA, Andres E, Pietrelli LA (2001) Treatment of 21 cases of inva-

M. Garnica and M. Nucci sive mucormycosis with amphotericin B colloidal dispersion. Eur J Clin Microbiol Infect Dis 20:460–466 19. Imhof A, Balajee SA, Fredricks DN, Englund JA, Marr KA (2004) Breakthrough fungal infections in stem cell transplant recipients receiving voriconazole. Clin Infect Dis 39: 743–746 20. Jahagirdar BN, Morrison VA (2002) Emerging fungal pathogens in patients with hematologic malignancies and marrow/ stem-cell transplant recipients. Semin Respir Infect 17:113–120 21. Junghanss C, Marr KA, Carter RA, Sandmaier BM, Maris  MB, Maloney DG, Chauncey T, McSweeney PA, Storb R (2002) Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoietic stem cell transplantation: a matched control study. Biol Blood Marrow Transplant 8: 512–520 22. Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai KR (2002) Therapeutic role of alemtuzumab (Campath-1 H) in patients who have failed fludarabine: results of a large international study. Blood 99:3554–3561 23. Labbe AC, Su SH, Laverdiere M, Pepin J, Patino C, Cohen S, Kiss T, Lachance S, Sauvageau G, Busque L, Roy DC, Roy J (2007) High incidence of invasive aspergillosis associated with intestinal graft-versus-host disease following nonmyeloablative transplantation. Biol Blood Marrow Transplant 13:1192–1200 24. Laros-van Gorkom BA, Huisman CA, Wijermans PW, Schipperus MR (2007) Experience with alemtuzumab in treatment of chronic lymphocytic leukaemia in the Netherlands. Neth J Med 65:333–338 25. Lass-Florl C, Griff K, Mayr A, Petzer A, Gastl G, Bonatti H, Freund M, Kropshofer G, Dierich MP, Nachbaur D (2005) Epidemiology and outcome of infections due to Aspergillus terreus: 10-year single centre experience. Br J Haematol 131:201–207 26. Lee DG, Choi JH, Choi SM, Yoo JH, Kim YJ, Min CK, Lee  S, Kim DW, Shin WS, Kim CC (2002) Two cases of disseminated mucormycosis in patients following allogeneic bone marrow transplantation. J Korean Med Sci 17: 403–406 27. Losee JE, Selber J, Vega S, Hall C, Scott G, Serletti JM (2002) Primary cutaneous mucormycosis: guide to surgical management. Ann Plast Surg 49:385–390 28. MacKenzie KM, Baumgarten KL, Helm BM, McFadden PM, Deduska NJ, Loss GE Jr, Eason JD (2002) Innovative medical management with resection for successful treatment of pulmonary mucormycosis despite diagnostic delay. J La State Med Soc 154:82–85 29. Maertens J, Lagrou K, Deweerdt H, Surmont I, Verhoef GE, Verhaegen J, Boogaerts MA (2000) Disseminated infection by Scedosporium prolificans: an emerging fatality among haematology patients. Case report and review. Ann Hematol 79:340–344 30. Maertens J, Maertens V, Theunissen K, Meersseman W, Meersseman P, Meers S, Verbeken E, Verhoef G, Van EJ, Lagrou K (2009)) Bronchoalveolar lavage fluid galactomannan for the diagnosis of invasive pulmonary aspergillosis in patients with hematologic diseases. Clin Infect Dis 49: 1688–1693

27  Emerging Fungal Infections 31. Marr KA, Carter RA, Boeckh M, Martin P, Corey L (2002) Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood 100:4358–4366 32. Marr KA, Carter RA, Crippa F, Wald A, Corey L (2002) Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 34:909–917 33. Marty FM, Lee SJ, Fahey MM, Alyea EP, Soiffer RJ, Antin JH, Baden LR (2003) Infliximab use in patients with severe graft-versus-host disease and other emerging risk factors of non-Candida invasive fungal infections in allogeneic hematopoietic stem cell transplant recipients: a cohort study. Blood 102:2768–2776 34. Meersseman W, Lagrou K, Maertens J, Van WE (2007) Invasive aspergillosis in the intensive care unit. Clin Infect Dis 45:205–216 35. Nath DS, Kandaswamy R, Gruessner R, Sutherland DE, Dunn DL, Humar A (2005) Fungal infections in transplant recipients receiving alemtuzumab. Transplant Proc 37:934–936 36. Nelson PE, Dignani MC, Anaissie EJ (1994) Taxonomy, biology, and clinical aspects of Fusarium species. Clin Microbiol Rev 7:479–504 37. Nucci M (2003) Emerging moulds: Fusarium, Scedosporium and Zygomycetes in transplant recipients. Curr Opin Infect Dis 16:607–612 38. Nucci M, Anaissie E (2007) Fusarium infections in immunocompromised patients. Clin Microbiol Rev 20:695–704 39. Nucci M, Anaissie E (2002) Cutaneous infection by Fusarium species in healthy and immunocompromised hosts: implications for diagnosis and management. Clin Infect Dis 35:909–920 40. Nucci M, Anaissie E (2006) Emerging fungi. Infect Dis Clin North Am 20:563–579 41. Nucci M, Anaissie E (2009) Infections in patients with multiple myeloma in the era of high-dose therapy and novel agents. Clin Infect Dis 49:1211–1225 42. Nucci M, Anaissie EJ, Queiroz-Telles F, Martins CA, Trabasso P, Solza C, Mangini C, Simoes BP, Colombo AL, Vaz J, Levy CE, Costa S, Moreira VA, Oliveira JS, Paraguay N, Duboc G, Voltarelli JC, Maiolino A, Pasquini R, Souza CA (2003) Outcome predictors of 84 patients with hematologic malignancies and Fusarium infection. Cancer 98: 315–319 43. Nucci M, Marr KA (2005) Emerging fungal diseases. Clin Infect Dis 41:521–526 44. Nucci M, Marr KA, Queiroz-Telles F, Martins CA, Trabasso P, Costa S, Voltarelli JC, Colombo AL, Imhof A, Pasquini R, Maiolino A, Souza CA, Anaissie E (2004) Fusarium infection in hematopoietic stem cell transplant recipients. Clin Infect Dis 38:1237–1242 45. Odabasi Z, Mattiuzzi G, Estey E, Kantarjian H, Saeki F, Ridge RJ, Ketchum PA, Finkelman MA, Rex JH, Ostrosky-Zeichner L (2004) Beta-D-glucan as a diagnostic adjunct for invasive fungal infections: validation, cutoff development, and performance in patients with acute myelogenous leukemia and myelodysplastic syndrome. Clin Infect Dis 39:199–205 46. Panackal AA, Imhof A, Hanley EW, Marr KA (2006) Aspergillus ustus infections among transplant recipients. Emerg Infect Dis 12:403–408

347 47. Pavie J, Lacroix C, Hermoso DG, Robin M, Ferry C, Bergeron A, Feuilhade M, Dromer F, Gluckman E, Molina JM, Ribaud P (2005) Breakthrough disseminated Aspergillus ustus infection in allogeneic hematopoietic stem cell transplant recipients receiving voriconazole or  caspofungin prophylaxis. J Clin Microbiol 43: 4902–4904 48. Perfect JR, Cox GM, Lee JY, Kauffman CA, de Repentigny L, Chapman SW, Morrison VA, Pappas P, Hiemenz JW, Stevens DA (2001) The impact of culture isolation of Aspergillus species: a hospital-based survey of aspergillosis. Clin Infect Dis 33:1824–1833 49. Perfect JR, Marr KA, Walsh TJ, Greenberg RN, Dupont B, de la Torre-Cisneros J, Just-Nubling G, Schlamm HT, Lutsar I, Espinel-Ingroff A, Johnson E (2003) Voriconazole treatment for less-common, emerging, or refractory fungal infections. Clin Infect Dis 36:1122–1131 50. Pfeiffer CD, Fine JP, Safdar N (2006) Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis 42:1417–1427 51. Racil Z, Kocmanova I, Lengerova M, Winterova J, Mayer J (2007) Intravenous PLASMA-LYTE as a major cause of false-positive results of platelia Aspergillus test for gala­ ctomannan detection in serum. J Clin Microbiol 45: 3141–3142 52. Revankar SG, Patterson JE, Sutton DA, Pullen R, Rinaldi MG (2002) Disseminated phaeohyphomycosis: review of an emerging mycosis. Clin Infect Dis 34:467–476 53. Saracli MA, Mutlu FM, Yildiran ST, Kurekci AE, Gonlum A, Uysal Y, Erdem U, Basustaoglu AC, Sutton DA (2007) Clustering of invasive Aspergillus ustus eye infections in a tertiary care hospital: a molecular epidemiologic study of an uncommon species. Med Mycol 45:377–384 54. Schutt P, Brandhorst D, Stellberg W, Poser M, Ebeling P, Muller S, Buttkereit U, Opalka B, Lindemann M, GrosseWilde H, Seeber S, Moritz T, Nowrousian MR (2006) Immune parameters in multiple myeloma patients: influence of treatment and correlation with opportunistic infections. Leuk Lymphoma 47:1570–1582 55. Singh N (2002) Imaging findings in invasive zygomycosis. Liver Transpl 8:306–307 56. Siwek GT, Pfaller MA, Polgreen PM, Cobb S, Hoth P, Magalheas-Silverman M, Diekema DJ (2006) Incidence of invasive aspergillosis among allogeneic hematopoietic stem cell transplant patients receiving voriconazole prophylaxis. Diagn Microbiol Infect Dis 55:209–212 57. Steinbach WJ, Benjamin DK Jr, Kontoyiannis DP, Perfect JR, Lutsar I, Marr KA, Lionakis MS, Torres HA, Jafri H, Walsh TJ (2004) Infections due to Aspergillus terreus: a multicenter retrospective analysis of 83 cases. Clin Infect Dis 39:192–198 58. Stergiopoulou T, Meletiadis J, Roilides E, Kleiner DE, Schaufele R, Roden M, Harrington S, Dad L, Segal B, Walsh TJ (2007) Host-dependent patterns of tissue injury in invasive pulmonary aspergillosis. Am J Clin Pathol 127: 349–355 59. Torres HA, Rivero GA, Lewis RE, Hachem R, Raad II, Kontoyiannis DP (2003) Aspergillosis caused by non-fumigatus Aspergillus species: risk factors and in vitro susceptibility compared with Aspergillus fumigatus. Diagn Microbiol Infect Dis 46:25–28

348 60. Tsiodras S, Samonis G, Boumpas DT, Kontoyiannis DP (2008) Fungal infections complicating tumor necrosis factor alpha blockade therapy. Mayo Clin Proc 83:181–194 61. Vagefi PA, Cosimi AB, Ginns LC, Kotton CN (2008) Cutaneous Aspergillus ustus in a lung transplant recipient: emergence of a new opportunistic fungal pathogen. J Heart Lung Transplant 27:131–134 62. Van Den NE, Michaux L, Layios N, Costantini S, Francart J, Lambert C, Sonet A, Andre M, Robert A, Ferrant A (2004) High incidence of complications after 2-chloro-2’-deoxyadenosine combined with cyclophosphamide in patients with advanced lymphoproliferative malignancies. Ann Hematol 83:356–363 63. Varkey JB, Perfect JR (2008) Rare and emerging fungal pulmonary infections. Semin Respir Crit Care Med 29:121–131 64. Vera A, Hubscher SG, McMaster P, Buckels JA (2002) Invasive gastrointestinal zygomycosis in a liver transplant recipient: case report. Transplantation 73:145–147 65. Virgili A, Zampino MR, Mantovani L (2002) Fungal skin infections in organ transplant recipients. Am J Clin Dermatol 3:19–35

M. Garnica and M. Nucci 66. Walsh TJ, Groll A, Hiemenz J, Fleming R, Roilides E, Anaissie E (2004) Infections due to emerging and uncommon medically important fungal pathogens. Clin Microbiol Infect 10(Suppl 1):48–66 67. Walsh TJ, Lutsar I, Driscoll T, Dupont B, Roden M, Ghahramani P, Hodges M, Groll AH, Perfect JR (2002) Voriconazole in the treatment of aspergillosis, scedosporiosis and other invasive fungal infections in children. Pediatr Infect Dis J 21:240–248 68. Wingard JR (1999) Opportunistic infections after blood and marrow transplantation. Transpl Infect Dis 1:3–20 69. Wingard JR (2007) New approaches to invasive fungal infections in acute leukemia and hematopoietic stem cell transplant patients. Best Pract Res Clin Haematol 20: 99–107 70. Yuen KY, Woo PC, Ip MS, Liang RH, Chiu EK, Siau H, Ho PL, Chen FF, Chan TK (1997) Stage-specific manifestation of mold infections in bone marrow transplant recipients: risk factors and clinical significance of positive concentrated smears. Clin Infect Dis 25:37–42

Candida Pneumonia in Patients with Hematological Neoplasia

28

Carlos Carvajal, Jordi Rello, and Jeffrey Lipman

Contents

28.1  Introduction

28.1

Introduction............................................................. 349

28.2

Epidemiology........................................................... 350

Advances in the management of hematological malignancies have resulted in marked improvements in life expectancy and the quality of patients’ lives. However, patients with malignancies are rendered highly susceptible to infection by virtue of their underlying diseases and their associated therapies, including chemotherapy, radiation therapy, and surgery. Traditionally, infection has accounted for up to 75% of deaths in patients with hematologic neoplasia. However, advances in prevention and treatment have decreased infectious-related death to about 50% [1, 2]. Infectious complications represent a major death risk during neutropenia; the lung is the most frequently involved site. Pneumonia is the most frequent lifethreatening infectious complication occurring during the course of neutropenia in patients with cancer. Lung infection can be caused by a variety of pathogens, including bacteria, viruses, protozoa, and fungi. Candida is the most frequent causative agent of invasive fungal infections in immunocompromised hosts. Candida is part of the normal human microbial flora localized in the skin, mucous membranes, digestive tract, and urogenital tract. In immunocom­promised hosts such as patients with hematologic neoplasia, Candida can be an opportunistic pathogen causing lifethreatening disseminated infections [3]. The ability of the Candida to alter its morphology between yeast and true hyphal growth forms is thought to contribute to its pathogenicity. The skin and mucosal surfaces are the first barriers in the host defense against fungal invasion, followed by neutrophil and macrophage activation,

28.3 Risk Factors for Invasive Pulmonary Candidiasis.............................................................. 350 28.4

Diagnosis.................................................................. 351

28.5

Treatment................................................................ 352

28.6

Conclusion............................................................... 355

References............................................................................ 355

C. Carvajal Critical Care Department, Hospital Pablo Tobon Uribe, Calle 78B #69-240 Medellín (Antioquia), Colombia - Suramérica, 43007 Tarragona, Spain e-mail: [email protected] J. Rello (*) Critical Care Department, Hospital Vall d’Hebron, CIBERES, Vall D’Hebron Institut Recerca (VHIR), Universitat Autonoma de Barcelona, Ps Vall d’Hebron 119-129 08035 Barcelona, Spain e-mail: [email protected] J. Lipman  Department of Intensive Care Medicine, Intensive Care Unit, Royal Brisbane and Women’s Hospital, Herston Road, Brisbane, Australia and Burns, Trauma, Critical Care Research Centre, University of Queensland, Australia e-mail: [email protected]

Supported in part by CIBERES 06/06/0036, AGAUR 09/SGR/920

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_28, © Springer-Verlag Berlin Heidelberg 2011

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factors usually preventing fungal dissemination [3]. Candida infection is not common in immunocompromised patients without neutropenia [4]. Although neutropenia is the most important predisposing factor for invasive candidiasis, other mechanisms that have been implicated are deficiencies in humoral and cellular immunity, impairments in mucosal defensive mechanisms, and functional alterations of neutrophils [5]. In these patients bloodstream infections and catheter-related infections are the most common types of Candida infections, and pneumonia is extremely uncommon. Invasive candidiasis has been associated with severe sepsis, septic shock, and multiorgan failure with clinical characteristics resembling those caused by bacterial pathogens [6].

28.2  Epidemiology Fungal infections have increased dramatically during the last decades. Candida has evolved as a prominent cause of infection in ICU patients. However Candida infection can easily be overestimated (Fig. 28.1), as the diagnosis of invasive candidiasis is difficult. With the exception of candidemia, diagnosis requires histological confirmation. For this reason, epidemiological data on Candida pneumonia are scarce and often unreliable [7].

Candidemia

Invasive candidiasis

The incidence of infection and/or fungal colonization in critically ill patients has increased over recent decades. In the United States, sepsis related to fungal infections has multiplied by threefold, from over 5,000 cases in 1979 to more than 16,000 in 2000 [8, 9]. This involves a significant increase of candidemia. Candida pneumonia was first described in 1771 by Rosen Von Rosenstein; later Castellani reported Candida pneumonia in tea tasters in Ceylon. Since then, there have been only scattered reports [10]. Candida pneu­ monia is rare, and it occurs most often in patients receiving immunosuppressive or broad-spectrum antibiotic ­therapy. Haron et al. [11], found an incidence of 0.4% among 7,725 patients, which is similar to Masur’s ­findings some years before (0.23%) [12]. In a search of the PubMed database (http://www.ncbi.nlm.nih.gov/ pubmed accessed 14 May 2009), 91 cases of Candida pneumonia (Table  28.1) confirmed by histopathology [2, 10, 11, 13–15] were identified. Although non-albicans species have emerged as significant pathogens in critically ill patients, Candida albicans continues causing the largest number of infections, representing more than half of all isolates in Candida pneumonia, followed by Candida tropicalis and Candida glabrata. Other species, such as Candida krusei and Candida parapsilosis, are less frequently isolated [2, 10, 11, 15]. With the exception of candidemia, the impact of invasive Candida infections, in terms of morbidity and mortality, has not been studied in great detail. Candida endophthalmitis is associated with a mortality rate estimated at 80% [16], and primary Candida pneumonia has a mortality rate up 70% [2, 11]. There are few identified factors associated with mortality in Candida pneumonia. Intubation and need for mechanical ventilation because of respiratory failure are associated with 90% mortality. Additionally, when antifungal therapy was started later (>10 days), mortality rose above 70% (p < 0.05) [2].

High grade colonization

Low grade colonization

Fig.  28.1  The spectrum of disease caused by Candida. Candidemia is the top of the iceberg. Invasive candidiasis includes Candida pneumonia. Colonization (high and low grade) is determined by number of sites with positive cultures

28.3 Risk Factors for Invasive Pulmonary Candidiasis Previous colonization by Candida in nonsterile sites has been identified as a risk factor for invasive infection [17]. Indeed, about 90% of patients with invasive Candida infection showed previous colonization of the

28  Candida Pneumonia in Patients with Hematological Neoplasia Table 28.1  Cases confirmed by histopathology of Candida pneumonia Prior steroids/ Study Patient type Prior broadimmunosuppres­spectrum sive treatment antibiotics

351

Organism

Cases

Mortality

Schröter et al. [13]

After liver transplantation

–

–

–

7

–

Mohsenifar et al. [10]

Primary malignant

20

16

20 C. albicans

20

–

Buff et al. [14]

Hematological malignancies

–

11

–

20

–

Haron et al. [11]

Primary malignant

28

15

11 C. albicans

31

84%

12

–

1

1

2 C. tropicalis 1 C. parapsilosis 18 not reported

von Eiff et al. [2]

Hematological malignancies

12

PetrocheilouPaschou et al. [15]

After heart transplantation

1

6

6 C. albicans 1 C. glabrata

1

respiratory tract by the same type of Candida [18, 19]. Risk factors for colonization are underlying disease, central venous catheterization, parenteral nutrition, exposure to broad-spectrum antimicrobials, acute ­pancreatitis, abdominal surgery, and gastrointestinal fistulas. Candida albicans pneumonia can originate in one of two ways. True Candida pneumonia is a hematogenously disseminated pulmonary infection along with involvement of other organs, often resulting in fungal emboli in the lung. The other form is rare and occurs after aspiration of oropharyngeal material, causing primary pneumonia. Although the lungs have innate mechanisms of defense that render them very resistant to tissue invasion by Candida sp., this is not so for nonfilamentous fungi, such as Aspergillus sp. Non-albicans Candida species are also an important cause of Candida pneumonia [2, 11, 15]. Fluconazole has been identified as a risk factor for the emergence of non-albicans Candida [20]. From a practical point of view, it is important to predict when Candida infection may be caused by species potentially resistant to fluconazole, i.e., C. glabrata or C. krusei. However C. glabrata or C. krusei infection also may occur in patients without previous exposure to this antimicrobial.

1 C. krusei

28.4  Diagnosis In the evaluation of acutely ill, immunocompromised patients with suspected pneumonia, a meticulous and thorough history and physical examination must be performed. Diagnosis confirmation and identification of underlying microorganisms is essential for appropriate therapy. Even though patients with advanced hematologic disease are at higher risk of developing pneumonia, this complication frequently affects patients with hematologic diseases at their onset. The diagnosis of Candida pneumonia can be difficult for a number of reasons: an impaired inflammatory response can reduce clinical or radiological signs; an etiological diagnosis is difficult to obtain because of the risk of hemorrhage due to thrombocytopenia. As a result, a considerable proportion of pulmonary fungal infections are not diagnosed ante mortem in cancer patients [21]. Several procedures are recommended for the identification of Candida infection: (1) clinical presentation and imaging, (2) culture of respiratory samples, (3) detection of circulating antigens, (4) detection of specific antibodies, (5) detection of metastatic seeds, and (5) histopathologic confirmation (Fig. 28.2). All the above-mentioned methods have their drawbacks: The clinical presentation is not specific; only

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Clinical presentation

Histopathologic confirmation

Imaging

Detection of seeds

Culture of respiratory samples

Detection Ag/Ab

Fig.  28.2  Procedures for reliable identification of Candida infection. Antigens (Ag), antibodies (Ab)

50% of blood cultures are positive in patients with systemic candidiasis [22], and detection methods for antigens have low sensitivity [18, 23, 24]. Similarly, the detection of antibodies against Candida also has limited value, because patients are immunosuppressed and therefore present with an impaired immune response, and finally there is an excess of false-positive results [25]. Clinical presentation is characterized by cough, expectoration of purulent secretions, occasional hemop­tysis and invariably hypoxemia [10]. Fever and progressive shortness of breath (and concomitant tachypnea) tend to be common symptoms, although in the neutropenic patient all these signs and symptoms are likely to be unimpressive or even absent. Fever appears in 80% of cases and leukocytosis in 50% (although there are patients with neutropenia), endophthalmitis in 9–15%, and cutaneous lesions or septic arthritis in less than 1% [26] (Fig. 28.3). Chest radiographs (CXR) should be obtained promptly in the patient with suspected pneumonia. However, the diagnostic yield of conventional CXR is poor, and compared with computer tomography (CT), conventional CXR manifests often too late to be the correct trigger for the start of therapy [27] (Table 28.2). CT scan increases the accuracy of diagnosing and typing of the pneumonia. If the pneumonic infiltrates are

located in the upper and lower lobes of the lungs or the lingula, there is a real risk that the pneumonia may be missed when CXR is performed. This obviously may lead to an erroneous treatment decision [28]. Heussel et al. [27], found in a series of neutropenic patients with fever of unknown origin and normal CXR that 60% of CT studies were indicative of pneumonia. In 54% of these studies, either clinical (chest radiography) or microbiologic documentation of pulmonary infiltration was possible. Sensitivity of CT was 87% (88% in transplant recipients), specificity was 57% (67%), and the negative predictive value was 88% (97%). Moreover, a time gain of 5 days using CT in comparison with the exclusive use CXR has been found. The primary diagnostic challenge is the differentiation of fungal colonization from fungal infection. The isolation of Candida from the respiratory tract samples ranges from 11% [29] to 52% [18], increasing its rate in mechanically ventilated patients up to 70% [30, 31]. Isolation of Candida in the bronchial tree reflects colonization, but in many occasions this “benign” Candida colonization may be unfairly categorized as Candida pneumonia. This reflects the extremely difficult confirmation of diagnosis of Candida pneumonia. The value of quantitative cultures of respiratory samples for yeasts is unknown [32]. Histological confirmation is the gold standard for diagnosis of Candida pneumonia. However, biopsy is difficult to perform, and autopsy studies aimed to estimate the incidence are biased by the refusal of next of kin to give the informed consent. For this reason it is still a matter of debate whether Candida is able to cause pneumonia in immunosuppressed but non-neutropenic patients [4].

28.5  Treatment Treatment of Candida pneumonia in neutropenic patients should be essentially the same as in non-neutropenic patients. The decision to initiate intensive care treatment has to take into account the prognosis of the underlying disease. Mortality in patients with hematological malignancies admitted to an ICU with Candida pneumonia is 70% [2, 11]. Treatment must be started immediately to improve tissue oxygenation, restore cardiovascular function, and improve other organ functions [33, 34].

28  Candida Pneumonia in Patients with Hematological Neoplasia Fig. 28.3  Clinical presentation in pneumonia by Candida in four series [2, 10, 11, 15]

353

80 70 60 50 % 40 30 20 10

H

yp

ox em

ia

Fe ve r

pn ea

ou gh C

ys D

nt le ru Pu

H

em

op ty

si s

sp ut um

0

Table 28.2  Radiographic findings in Candida pneumonia Radiographic % Patients findings Buff Haron PetroMohse[14] [11] cheilou ni far Paschou [10] [15] Diffuse bilateral infiltrates with confluent areas of air space consolidation

16/20

15/31

–

8/20

Localized pneumonia (1 or more lobes)

4/20

16/31

1/1

12/20

Effusion pleural

5/20

–

–

5/20

Although targeted treatment is the best therapy for Candida pneumonia, there are four approaches to antimycotic therapy: prophylaxis, preemptive treatment, empiric treatment, and targeted treatment [26]. Targeted treatment requires positive cultures and directed antifungal therapy. Currently, there are several antifungal drugs available for the treatment of Candida infections in general and, in particular, in high-risk subjects such as the critically ill. These

include deoxycholate preparation and lipid-based formulations of amphotericin B, azoles like fluconazole, itraconazole or voriconazole, and echinocandins. Unfortunately, amphotericin deoxycholate plus flucytosine are the only option with clinical evidence [2]. Conventional deoxycholate amphotercin B (AmB-d) is an effective drug in treating systemic fungal infections. Nevertheless, it can produce a wide variety of severe adverse events such as renal failure. Because of this, it should not be used in critically ill patients [35]. Nephrotoxicity is the most common serious adverse effect associated with AmB-d therapy, resulting in acute renal failure in up to 50% of recipients [36, 37]. However, continuous infusions (24 h) of amphotericin B are significantly better tolerated and can reduce nephrotoxicity and side effects without increasing mortality [38], although one prospective study by Ellis et  al. concluded that infusion rates for 4  h did not ­modify amphotericin B toxicity [39]. Lipid-based formulations of amphotericin B (LF-AmB) have been developed and approved for use in humans. There are three formulations commercially available. These agents possess the same spectrum of activity as AmB-d with less nephrotoxicity [36, 37]. The new azoles, fluconazole in particular, offer a form of treatment that is less toxic than AmB-d and equally effective, provided that they are used at

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adequate doses (Table 28.3) and that it is possible to identify high-risk patients requiring “empiric” treatment [26]. Fluconazole can be chosen for initial empiric therapy in clinically stable patients who have not received prior azoles. However, if C. glabrata is isolated, the patient should be started on high-dose fluconazole (>12  mg/kg/day or >800  mg/day for a 70-kg patient) or switched to echinocandins or amphotericin B, although, there are few data supporting this recommendation [40]. On the other hand, certain non-albicans Candida species are less susceptible to fluconazole, and some Candida albicans can be resistant to fluconazole. There are other azoles with activity against Candida species. Posaconazole and voriconazole do not have an indication for primary Candida pneumonia therapy.

Voriconazole is effective for both mucosal and invasive candidiasis, but it has not been proven in clinical trials. Its clinical use has been primarily for step-down oral therapy in patients with infection due to C. krusei and fluconazole-resistant, voriconazole-susceptible C. glabrata. However, drug-drug interactions are common with voriconazole and should be considered when initiating and discontinuing treatment with this compound [41]. Echinocandins, caspofungin, anidulafungin, and micafungin are available only as parenteral preparations. These drugs have fungicidal activity against Candida targeting the fungal cell wall. The absence of this target in mammalian cells probably contributes to its favorable safety profile with few adverse effects. Echinocandins are at least as effective as amphotericin

Table 28.3  Antifungal agents approved for invasive candidiasis treatment Antifungal Loading doses Maintenance doses

Comments

Polyenes Deoxycholate amphotericin B

1 mg/kg/day

1 mg/kg/day

It can cause renal insufficiency

Amphotericin B lipid complex

5 mg/kg/day

5 mg/kg/day

Dosage should be adjusted in renal insufficiency

Amphotericin B liposomal

6 mg/kg/day

6 mg/kg/day

Dosage should be adjusted in renal insufficiency

Amphotericin B colloidal dispersion

4–6 mg/kg/day

4–6 mg/kg/day

Dosage should be adjusted in renal insufficiency

800 mg × 1 doses

400 mg/day

12 mg/kg

6 mg/kg/day

Dosage should be adjusted in renal or hepatic insufficiency

200 mg/kg/12 h

200 mg/kg/12 h

3 mg/kg/12 h

3 mg/kg/12 h

400 mg/day × 2 doses

200 mg/12 h

6 mg/kg/day × 2 doses

3 mg/kg/12 h

70 mg/day × 1 doses

50 mg/day

Azoles Fluconazole

Itraconazole

Voriconazole

Dosage should be adjusted in renal or hepatic insufficiency Dosage should be adjusted in renal or hepatic insufficiency

Echinocandins Caspofungin

Dosage reduction for patients with moderate to severe hepatic dysfunction. No required dosage adjustment for renal insufficiency or dyalisis

Anidulafungin

200 mg/day × 1 doses

100 mg/day

No required dosage adjustment for renal insufficiency or dyalisis

Micafungin

100 mg/day

100 mg/day

No required dosage adjustment for renal insufficiency or dyalisis

28  Candida Pneumonia in Patients with Hematological Neoplasia

B for the treatment of invasive candidiasis and even more so for candidemia [41, 42]. The minimal inhibitory concentrations (MICs) of the echinocandins are low for a broad spectrum of Candida species, as they retain activity against isolates with resistance to azoles or polyenes [41, 42]. However, clinical trials of echinocandins treatment in Candida pneumonia have not been done yet (Table 28.3). Flucytosine demonstrates broad antifungal activity against most Candida species, with the exception of C. krusei. However, flucytosine is rarely administered as a single agent, but is usually given in combination with AmB for patients with pneumonia by Candida [10, 11].

28.6  Conclusion Infectious complications are common and represent a major death risk during neutropenia. Pneumonia is extremely uncommon, but associated with high mortality. Isolation of Candida from the respiratory tract samples reflects colonization of the bronchial tree (or sample contamination from oropharynx). Therefore, diagnosis of pneumonia by Candida should require histological confirmation. Finally, if documented, antifungal agents for treatment of pneumonia by Candida should essentially be the same as for invasive candidiasis. Competing Interests: The authors declare that they have no competing interests.

References   1. Daly JS, Finberg RW (2008) Acute infection in the immunocompromised host. In: Irwin RS, Rippe JM (eds) Irwin and Rippe’s intensive care medicine, 6th edn. Lippincott Williams & Wilkins, Philadelphia   2. von Eiff M, Roos N, Fegeler W et  al (1996) Hospitalacquired candida and aspergillus pneumonia – diagnostic approaches and clinical findings. J Hosp Infect 32:17–28   3. Galvan B, Mariscal F (2006) Epidemiologia de la candidemia en UCI. Rev Iberoam Micol 23:12–15   4. Vélez L, Correa LT, Maya MA et al (2007) Diagnostic accuracy of bronchoalveolar lavage samples in immunosuppressed patients with suspected pneumonia: analysis of a protocol. Respir Med 101:2160–2167   5. Rossini F, Verga M, Pioltelli P et  al (2000) Incidence and outcome of pneumonia in patients with acute leukemia

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receiving first induction therapy with anthracycline-containing regimens. Haematologica 85:1255–1260   6. Pappas PG, Rex JH, Sobel JD (2004) Infectious diseases Society of America. Guidelines for treatment of candidiasis. Clin Infect Dis 38:161–189   7. Kishikawa H, Tojima H, Tokudome T (1997) Microscopic polyangiitis and pulmonary fibrosis in a patient who died of Candida pneumonia and intra-alveolar hemorrhage. Nihon Kyobu Shikkan Gakkai Zasshi 35:915–920 [Japanese – Abstract]   8. Martin GS, Mannino DM, Eaton S et al (2003) The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 348:1546–1554   9. Trick WE, Fridkin SK, Edwards JR et  al (2002) National Nosocomial Infections Surveillance System. Secular trend of hospital-acquired candidemia among intensive care unit patients in the united states during 1989–1999. Clin Infect Dis 35:627–630 10. Mohsenifar Z, Chopra SK, Johnson BL et al (1979) Candida pneumonia: experience with 20 patients. West J Med 131: 196–200 11. Haron E, Vartivarian S, Anaissie E et  al (1993) Primary Candida pneumonia. Experience at a large cancer center and review of the literature. Medicine (Baltimore) 72:137–142 12. Masur H, Rosen PP, Armstrong D (1977) Pulmonary disease caused by Candida species. Am J Med 63:914–925 13. Schröter GP, Hoelscher M, Putnam CW et al (1977) Fungus infections after liver transplantation. Ann Surg 186: 115–122 14. Buff SJ, McLelland R, Gallis HA et al (1982) Candida albicans pneumonia: radiographic appearance. AJR Am J Roentgenol 138:645–648 15. Petrocheilou-Paschou V, Georgilis K, Kontoyannis D et  al (2002) Pneumonia due to Candida krusei. Clin Microbiol Infect 8:806–809 16. Menezes AV, Sigesmund DA, Demajo WA et  al (1994) Mortality of hospitalized patients with Candida endophthalmitis. Arch Intern Med 154:2093–2097 17. Pittet D, Monod M, Suter PM et al (1994) Candida colonization and subsequent infections in critically ill surgical patients. Ann Surg 220:751–758 18. Bär W, Hecker H (2002) Diagnosis of systemic Candida infections in patients of the intensive care unit. Significance of serum antigens and antibodies. Mycoses 45:22–28 19. Voss A, Hollis RJ, Pfaller MA et al (1994) Investigation of the sequence of colonization and candidemia in nonneutropenic patients. J Clin Microbiol 32:975–980 20. Almirante B, Rodríguez D, Park BJ, Barcelona Candidemia Project Study Group et  al (2005) Epidemiology and ­predictors of mortality in cases of Candida bloodstream infection: results from population-based surveillance, barcelona, Spain, from 2002 to 2003. J Clin Microbiol 43: 1829–1835 21. Sickles EA, Greene WH, Wiernik PH (1975) Clinical presentation of infection in granulocytopenic patients. Arch Intern Med 135:715–719 [Abstract] 22. Vincent JL, Anaissie E, Bruining H et al (1998) Epidemiology, diagnosis and treatment of systemic Candida infection in surgical patients under intensive care. Intensive Care Med 24:206–216

356 23. Yeo SF, Zhang Y, Schafer D et al (2000) A rapid, automated enzymatic fluorometric assay for determination of D-arabinitol in serum. J Clin Microbiol 38:1439–1443 24. Allaouchiche B, Coronel B, Gagnieu MC et  al (2004) Cytokine levels in bronchoalveolar lavage fluid and blood of neutropenic patients with pneumonia. Bull Cancer 91: 77–80 25. Petri MG, König J, Moecke HP, Paul-Ehrlich Society for Chemotherapy, Divisions of Mycology and Pneumonia Research et al (1997) Epidemiology of invasive mycosis in ICU patients: a prospective multicenter study in 435 nonneutropenic patients. Intensive Care Med 23:317–325 26. De Bellis P, Bonfiglio M, Gerbi G et  al (2003) High-dose fluconazole therapy in intensive care unit. Minerva Anestesiol 69:145–152 27. Heussel CP, Kauczor HU, Heussel GE et al (1999) Pneumonia in febrile neutropenic patients and in bone marrow and blood stem-cell transplant recipients: use of high-resolution computed tomography. J Clin Oncol 17:796–805 28. Syrjälä H, Broas M, Suramo I et al (1998) High-resolution computed tomography for the diagnosis of communityacquired pneumonia. Clin Infect Dis 27:358–363 29. Weinberger M, Sacks T, Sulkes J et al (1997) Increasing fungal isolation from clinical specimens: experience in a university hospital over a decade. J Hosp Infect 35:185–195 30. Azoulay E, Timsit JF, Tafflet M et al (2006) Candida colonization of the respiratory tract and subsequent pseudomonas ventilator-associated pneumonia. Chest 129:110–117 31. El-Ebiary M, Torres A, Fàbregas N et al (1997) Significance of the isolation of Candida species from respiratory samples in critically ill, non-neutropenic patients. An immediate postmortem histologic study. Am J Respir Crit Care Med 156:583–590 32. Rello J, Esandi ME, Díaz E et al (1998) The role of Candida sp isolated from bronchoscopic samples in nonneutropenic patients. Chest 114:146–149 33. Penack O, Beinert T, Buchheidt D, German Society of Hematology and Oncology et al (2006) Management of sepsis in neutropenia: guidelines of the infectious diseases work-

C. Carvajal et al. ing party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Hematol 85: 424–433 34. Benoit DD, Vandewoude KH, Decruyenaere JM et al (2003) Outcome and early prognostic indicators in patients with a hematologic malignancy admitted to the intensive care unit for a life-threatening complication. Crit Care Med 31: 104–112 35. Garnacho-Montero J, Díaz-Martín A, Cayuela-Dominguez A (2008) Management of invasive Candida infections in non-neutropenic critically ill patients: from prophylaxis to early therapy. Int J Antimicrob Agents 32(Suppl 2): S137–S141 36. Deray G (2002) Amphotericin B nephrotoxicity. J Antimicrob Chemother 49(Suppl 1):37–41 37. White MH, Bowden RA, Sandler ES et al (1998) Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia. Clin Infect Dis 27:296–302 38. Eriksson U, Seifert B, Schaffner A (2001) Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomised controlled trial. BMJ 322:579–582 39. Ellis ME, al-Hokail AA, Clink HM et  al (1992) Doubleblind randomized study of the effect of infusion rates on toxicity of amphotericin B. Antimicrob Agents Chemother 36: 172–179 40. Chen H, Suda KJ, Turpin RS et al (2007) High- versus lowdose fluconazole therapy for empiric treatment of suspected invasive candidiasis among high-risk patients in the intensive care unit: a cost-effectiveness analysis. Curr Med Res Opin 23:1057–1065 41. Pappas PG, Kauffman CA, Andes D et al (2009) Infectious Diseases Society of America. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 48:503–535 42. Mora-Duarte J, Betts R, Rotstein C, Caspofungin Invasive Candidiasis Study Group et al (2002) Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 347:2020–2029

Parasitic Lung Infections

29

Jean-François Timsit, Jean-Paul Brion, and Hervé Pelloux

Contents 29.1 Host–Parasite Interaction...................................... 357 29.1.1 Toxoplasmosis.......................................................... 358 29.1.2 Strongyloidiasis........................................................ 359 29.2 Toxoplasmosis.......................................................... 359 29.2.1 Clinical Presentation................................................. 360 29.3 Strongyloidiasis....................................................... 361 29.3.1 Clinical Presentation................................................. 361 29.4 Treatment of Strongyloidiasis and Toxoplasmosis.................................................. 362 29.5 Toxoplasmosis.......................................................... 362 29.5.1 Possible Alternative Regimens................................. 362 29.5.2 Management of Pulmonary Toxoplasmosis in Hematopoietic Stem Cell Transplant Recipients................................................................. 363 29.5.3 Primary Prophylaxis................................................. 363 29.6 Strongyloidiasis....................................................... 363 29.6.1 Management of Hyperinfection or Disseminated Infection.................................................................... 364 29.6.2 Preventive Therapy................................................... 364 29.6.3 Preventing Disease and Disease Recurrence............ 364 29.6.4 Clinical Vignette....................................................... 365 References............................................................................ 366

J.-F. Timsit (*) Medical Polyvalent ICU, Albert Michallon University Hospital, BP 217, 38043, Grenoble Cedex 09, France and Inserm U 823, Team 11: Epidemiology of Cancer and Critical Illnesses, Grenoble, France e-mail: [email protected] J.-P. Brion Infectious Diseases Department, Albert Michallon University Hospital, Grenoble, France e-mail: [email protected] H. Pelloux Department of Mycology, Albert Michallon University Hospital, Grenoble, France e-mail: hpelloux@chu-grenoble

Pulmonary involvement with eukaryotic parasites in patients with hematological malignancies is less common than infections by bacteria or other eukaryotic pathogens such as fungi (mainly Pneumocystis, Aspergillus, and Candida). However, parasitic infections in immunocompromised patients are associated with a high morbidity and mortality rates if not prevented or diagnosed and treated in time [1–4]. These infections are rare or restricted to specific geographic areas in patients with hematological malignancies. One of the main features of parasitic infections is dissemination, which may be confused with another opportunistic infection, resulting in diagnostic delays. Two parasitic lung infections are sufficiently frequent to be described in detail, namely, toxoplasmosis and stongyloidiasis.

29.1 Host–Parasite Interaction The complexity of host–parasite interactions can explain, to some extent, the difficulties encountered in preventing, diagnosing, and treating parasitic infections in severely immunocompromised patients. These interactions vary widely across parasites, as these pathogens differ in their life cycles and structures, and induce host responses that do not involve the same pathways and mechanisms. The two parasites that deserve special attention in patients with hematological malignancies are the protozoan Toxoplasma gondii and the nematode Stongyloides stercoralis. Here, we describe the main characteristics of the host–parasite interactions that explain the clinical and biological features observed in hematological malignancy patients infected by these parasites.

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_29, © Springer-Verlag Berlin Heidelberg 2011

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29.1.1 Toxoplasmosis The relationship between T. gondii and its host is very complex [5, 6]. In immunocompetent patients, the host and parasite reach an equilibrium, as shown by the fact that chronic asymptomatic T. gondii infection is found in 50% of individuals in France. However, when the host immune responses are depressed (e.g., by AIDS or a hematological malignancy), the reactivation of latent parasite forms (bradyzoites) from quiescent cysts to virulent parasites (tachyzoites, Figs. 29.1 and 29.2) can lead to serious lesions in the brain, lungs, or other organs. The reactivated parasites may occur locally or disseminate via the bloodstream. Globally, host–parasite interactions depend on several factors, related both to the parasite and to the patient. Among parasite-related factors, the population structure of T. gondii allows the differentiation of three main lineages (types I, II, and III strains) and of nonarchetypal and highly virulent strains found mainly in South America [7]. These virulent strains can cause clinical lesions in immunocompetent patients that are as serious as those seen immunocompromised patients with disseminated type-II strain disease. Type II strains are found in more than 90% of the toxoplasmosis cases in western countries. Pathogenicity of type II strains occurs almost only in immunocompromised individuals and patients with congenital toxoplasmosis. Among patient-related factors, chronic infection is the main source of clinical toxoplasmosis in patients with hematological malignancies, and new infections are very rare. The decrease in host immune control leads to cyst rupture (in the brain and muscles),

Fig.  29.1  Dividing T. gondii tachyzoites (endodyogeny). Electronic microscopy (Photograph H. Pelloux, E. Brambilla for ANOFEL, with permission)

Fig.  29.2  Toxoplasma gondii. Tachyzoite (May-GrünwaldGiemsa) in bronchoalveolar lavage fluid (Photograph P. Marty for ANOFEL, with permission)

conversion from bradyzoites to tachyzoites, and development of local abscesses and/or hematogenous dissemination. Briefly, in immunocompetent patients, the process that leads to parasite encystation is driven by both innate and adaptive immune processes, with the balance between pro- and antiinflammatory cytokines being of paramount importance in reaching the equilibrium necessary for both host and parasite survival. The encysted quiescent parasites are protected from the immune response of the host. Taken as a whole, cellular immunity, macrophages, T lymphocytes, NK cells, and associated cytokines (mainly IFNg) are the main immune elements involved in controlling T. gondii infection. However, not all T-cell-deficient patients contract clinical toxoplasmosis, as the genetic background of the patient and parasite also plays a role. Therefore, the probability of clinical toxoplasmosis occurring cannot be predicted in the individual patient. In immunocompromised patients with hematological malignancies, lung involvement is due to hematogenous dissemination of the parasites, as pulmonary tissues are not known to harbor chronic Toxoplasma cysts. Recent data indicate that patients with hematological malignancies may experience T. gondii parasitemia without patent clinical symptoms [8, 9]. This possibility should be considered in patients known to be seropositive for T. gondii before the onset of the hematological malignancy and is of importance for interpreting laboratory tests used to diagnose toxoplasmosis in these patients. Immune reconstitution after bone marrow transplantation or remission of the malignancy leads to the development of a new host–parasite equilibrium and removes the risk of cyst reactivation.

29  Parasitic Lung Infections

29.1.2 Strongyloidiasis S. stercoralis is an intestinal nematode with a highly complex life cycle. It can persist in humans for decades and can lead to a fulminant hyperinfection syndrome if the host becomes immunosuppressed [3]. Thus, the main risk for patients with hematological malignancies in western countries is progression of chronic strongyloidiasis that was present before onset of the malignancy. Primary infection, transmission via an allogeneic transplant, and nosocomial transmission are exceedingly rare [10]. The chronic nature of strongyloidiasis, which is unique among nematodes, is due to the fact that S. stercoralis larvae can cause autoinfection: the eggs hatch in the intestine, releasing larvae that penetrate the intestinal wall and follow the normal infective cycle if the host is immunocompetent. This mechanism can lead to decades-long infection without re-infection in endemic areas. The normal life cycle includes a pulmonary step in which the filariform larvae are carried to the alveolar spaces via the circulatory system, then reach the pharynx and are swallowed to reach the intestine. In immunocompetent patients, the pulmonary step is most often asymptomatic. Furthermore, incomplete host–parasite equilibrium, less perfect than that seen in T. gondii infection, is induced, and the number of parasitic larvae is controlled to some extent. The infection cycle is not stopped, but its importance is limited. The widespread use of immunosuppressive therapy and the chronicity of strongyloidiasis make hyperinfection a clinically important problem even in nonendemic countries where migrant people live. Risk factors for hyperinfection and disseminated disease include impaired cell-mediated immunity, chronic corticosteroid therapy, hematopoietic stem cell transplantation, hematological malignancies such as lymphoma, human T-lymphotropic virus type 1 infection, hypogammaglobulinemia, and solid organ transplantation [11]. The most common risk factor is corticosteroid use, which results in eosinopenia, hampering the eosinophil-specific immune response against S. stercoralis. Of note, despite the overlap in endemic regions between HIV infection and strongyloidiasis, the incidence of strongyloidiasis is not higher than in the non-HIV-infected population. Eosinophils and interleukin-5 are known to be important components of the immune response to S. stercoralis infection. Activated eosinophils kill helminthic parasites in vitro, and interleukin-5-knockout CB57BL/6 mice

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exhibit increased susceptibility to stronglyoidiasis [12]. In patients with hematological malignancies, immunosuppression leads to loss of the host-parasite equilibrium with a marked increase in the activity of the normal life cycle that considerably augments the number of larvae disseminating into the body. The number of larvae in the lung and alveolar space leads to pulmonary function impairments that can progress to respiratory failure and death. S. stercoralis hyperinfection after solid organ transplantation can coincide with corticosteroid use to prevent graft rejection and usually manifests between 1 and 3 months after transplantation. However, S. stercoralis hyperinfection manifests earlier in hematopoietic stem cell transplant recipients, owing to their profound immunosuppression [4].

29.2 Toxoplasmosis Pulmonary toxoplasmosis is a well-known entity [13] that has been reported in immunocompetent patients, but chiefly affects the rapidly growing number of immunocompromised patients with cell-mediated immune deficiencies. In the 1990s, most of the patients with pulmonary toxoplasmosis had AIDS and a history of other AIDS-related infections. Patients with T. gondii pneumonia had a higher mortality rate than did patients with extra-pulmonary disease, with a median survival of 150 days after the diagnosis [14]. As progress was made in means of controlling HIV infection, the populations chiefly affected with pulmonary toxoplasmosis became organ transplantation recipients and patients with hematological malignancies. Allogeneic hematopoietic stem cell transplant recipients are at very high risk, whereas toxoplasmosis is rare in autologous stem cell transplant recipients. In bone marrow transplant recipients, the incidence of pulmonary toxoplasmosis varies markedly, from 0.28% to 4% of patients [15]. The infection rate is highest in countries where the prevalence of toxoplasmosis is high in the general population. However, when only seropositive recipients are considered, the incidence ranges from 1.9% to 5.7% [16]. The main risk factors are pretransplantation seropositivity of the recipient, allogeneic transplant, and graft versus host disease (requiring intensified immunosuppressive therapy) [2]. Myeloablative conditioning and conditioning with

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high-dose total body irradiation increase the risk of T. gondii reactivation [17]. Of note, alentuzumab, a new agent to treat lymphoproliferative disorders, might increase the risk of opportunistic infections via lysis of lymphocytes and other CD52-expressing cells through complement activation and antibody-dependent cellmediated toxicity [18, 19]. In a review of 81 allogeneic stem cell transplant recipients with toxoplasmosis [16], the median time to disease onset was 2 months after transplantation. Fewer than 10% of cases occurred during the first month and fewer than 15–20% after day 100. In bone marrow transplant recipients, disseminated toxoplasmosis carries a poorer prognosis than does cerebral toxoplasmosis, with a 5.28-fold increase in the odds of dying [20]. Of 55 patients with disseminated toxoplasmosis after bone marrow transplantation, only four survived, yielding a 93% mortality rate. This poor prognosis emphasizes the need for appropriate primary prevention in individuals at risk for the disease. Pulmonary toxoplasmosis is usually related to dissemination from another site rather than as the only disease location.

29.2.1 Clinical Presentation The clinical presentation is relatively nonspecific. Fever is usually present, and dyspnea and cough are reported in one-third of cases. Chest roentgenographs generally show diffuse interstitial infiltrates (see Sect. 19.6.4), but micronodular or nodular infiltrates are common also. Less common findings include cavitary infiltrates, lobar pneumonia, and pleural effusion [21]. High-resolution CT usually shows bilateral groundglass opacities with superimposed septal thickening and intralobular linear opacities [21]. Since the central nervous system is the most typical target of toxoplasmosis, neurological abnormalities are common, although nonspecific. They may include mental status changes and seizures with or without focal deficits [20]. Chorioretinitis may occur also. The clinical picture is frequently associated with multiple organ failure, in particular acute respira­tory distress syndrome, shock, and severe acute

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thrombocytopenia due to disease dissemination [22, 23] or hemophagocytic syndrome [1]. The first step of the diagnosis of toxoplasmosis in patients with hematological malignancies takes place before the development of deep immunosuppression. Since clinical toxoplasmosis usually results from reactivation of chronic infection, a serological test for T. gondii should be performed. Seropositive patients are at risk for reactivation, while seronegative patients are not, as they have no cysts in their brain and muscles [16]. Although primary prophylaxis with sulfamethoxazole/trimethoprim is not always effective in preventing toxoplasmosis, absence of such prophylaxis after bone marrow transplantation supports a diagnosis of toxoplasmosis. Proof of chronic infection consists in the detection of specific anti-T. gondii IgG in peripheral blood. When pulmonary toxoplasmosis is suspected in a previously seropositive patient with a hematological malignancy, the responsibility of T. gondii in the lung lesions must be confirmed. Extremely high levels of serum lactate dehydrogenase have been reported in patients with severe T. gondii pneumonia or disseminated disease and should prompt specific diagnostic procedures. The demonstration of tachyzoites by microscopic examination of the sputum [24], bronchoalveolar lavage fluid, or bone marrow aspirates remains the simplest means of establishing the diagnosis. Now, the diagnosis can also be made using real-time PCR on blood, cerebrospinal fluid, or, more invasively, from fluid recovered after fiberoptic bronchoscopy and bronchoalveolar lavage [24, 25]. The most efficient technique to date for T. gondii detection is PCR [16, 23]. PCR is sufficiently sensitive to detect very small amounts of parasite, and quantitative real-time techniques can estimate the parasite load in lungs and help to monitor treatment efficacy, although no validated reference standard exists for interpreting the results. Thus, whatever the technique used, the presence of T. gondii in pulmonary samples from a patient with a hematological malignancy constitutes proof of pulmonary toxoplasmosis. However, the diagnosis of toxoplasmosis is often more complex in these patients. Lung involvement with T. gondii can also be strongly suspected when suggestive clinical and imaging signs are present and PCR in the peripheral blood or antibody titer changes over time indicate parasite dissemination [8].

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29.3 Strongyloidiasis Strongyloidiasis is present in temperate, tropical, and subtropical climates. It is endemic in sub-Saharan Africa, the West Indies, South America, Southeast Asia, Bangladesh, Pakistan, and the southeastern United States, as well as in eastern European countries such as Romania and the Mediterranean countries [3, 4]. The global prevalence of strongyloidiasis is unclear and varies between 30 million and 100 million people infected [3]. The overall rate of S. stercoralis infection was 1 per 10,000 patients with newly diagnosed cancer in the United States [26, 27]. Hyperinfection occurs when immune suppression develops in a patient who has chronic strongyloidiasis. Although malnutrition remains the major secondary cause worldwide, in the developed world iatrogenic immune suppression is an important precipitant. Transplant recipients are at risk for developing S. stercoralis hyperinfection syndrome related to chronic intestinal S. stercoralis infection, acquisition of primary S. stercoralis infection in endemic areas, or transmission via an allogeneic transplant. Progression of chronic intestinal infection present before transplantation appears to be the most common mechanism. The low rate of strongyloidiasis after hematopoietic stem cell transplantation can be explained by routine screening for the parasite and the use of prophylactic treatment before transplantation. As with toxoplasmosis, the detection of chronic S. stercoralis infection before deep immunosuppression develops is crucial to prevent reactivation of the parasitic disease [3, 28]. Screening for chronic strongyloidiasis involves careful history-taking with attention to all trips to possibly endemic areas and to clinical symptoms consistent with strongyloidiasis. Laboratory screening involves serological testing for specific IgG antibodies, as peripheral eosinophilia may be intermittent [29, 30]. An enzyme-linked immunosorbent assay (ELISA) for detecting serum immunoglobulin G (IgG) against filariform S. stercoralis larvae has 95% sensitivity and negative predictive value. However, the S. stercoralis antibody test can show cross-reactivity with other helminth infections, such as filariasis, ascariasis, and schistosomiasis, leading to poor specificity of the test. In addition, S. stercoralis antibody testing cannot discriminate between past and current strongyloidiasis

Fig. 29.3  Rhabditoid larvae of Strongyloides stercoralis in stool (Photograph P. Le Pape for ANOFEL, with permission)

[12]. Finally, S. stercoralis antibody testing can be falsely negative in immunocompromised patients. The detection of parasite larvae in stool samples remains of main importance, although sensitivity is low if a single sample is tested. Detection relies chiefly on microscopy in routine practice, but molecular techniques are being developed and have produced promising results [31]. Stool sample examination (ideally three different samples) should be repeated if possible in an expert laboratory, as this increases sensitivity to 60–70% and perhaps higher in immunocompromised patients, which is worth the additional time needed. Concentration techniques such as the Baermann technique and stool culture technique must be used to increase the sensitivity of the test (Fig. 29.3).

29.3.1 Clinical Presentation The first step is careful history-taking for a history of stays in endemic regions and of S. stercoralis infestation. More than 50% of patients infected with S. stercoralis are asymptomatic, and 75% have fluctuating mild (5–15%) eosinophilia [32]. Other rare but classical symptoms involve the skin, gastrointestinal tract, and respiratory system. The typical skin lesion is a migratory, serpiginous, urticarial rash (larva currens or creeping larvae) due to larvae invading the skin, particularly of the buttocks, trunk, and inguinal regions. A history of intermittent hypereosinophilia, especially before immunosuppressive treatment initiation, should be sought carefully.

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Hyperinfection syndrome develops when immunosuppression allows intensification of the normal life cycle of the parasite, causing massive increases in the amounts of larvae produced. The larvae proliferate massively in the duodenum, migrate through the bowel wall, and travel through the venous system to the lungs and back to the small bowel. This can produce worsening pulmonary function impairments that start with wheezing and, in some patients, progress to acute respiratory distress syndrome, frequently accompanied by intra-alveolar hemorrhage leading to intractable respiratory failure and death. Gastrointestinal symptoms, such as dyspepsia, diarrhea, constipation, severe ileus, and gastrointestinal bleeding, may occur concomitantly. Hyperinfection syndrome is frequently accompanied with gram-negative enteric bacteremia caused by larvae migrating from the bowel through the venous system. S. stercoralis dissemination through the venous system to other locations in the body may also result in bacterial translocation to other organs, causing meningitis, cholecystitis, or liver abscesses. The presence of gram-negative sepsis is in itself life-threatening and may obscure the presence of disseminated S. stercoralis infection. When hyperinfection syndrome is suspected, the diagnosis must be made without delay. In this situation, there is usually no eosinophilia. The chest X-ray shows diffuse alveolar infiltrate consistent with intraalveolar hemorrhage. The presence of concurrent bacterial or fungal sepsis complicates the diagnosis of strongyloidiasis. The medical biologist must be informed of the suspected diagnosis. The techniques used are very simple and easy to perform, as the larval lung burden is high. Direct microscopic examination of wet mount preparations of sputum or bronchoalveolar lavage fluid is sufficient to establish the diagnosis and can be performed in any medical laboratory.

29.4 Treatment of Strongyloidiasis and Toxoplasmosis Acute disseminated infections caused by these two parasites require the prompt administration of antiparasitic drugs and the discontinuation or reduction of the immunosuppressive treatments if possible. Empiric or preemptive treatment is often needed before the diagnosis is confirmed. In this situation, the antiparasitic

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treatment is usually combined with an antibiotic or antiviral agent.

29.5 Toxoplasmosis The currently recommended anti-T. gondii drugs act against the tachyzoites and therefore do not eradicate the encysted forms. Consequently, secondary prophylaxis is required. Extensive studies in patients with AIDS have evaluated the treatment of toxoplasmosis, most notably manifesting as encephalitis or brain abscesses. This experience has been extrapolated to other immunodeficient patients. The treatment combines either sulfadiazine or clindamycin with pyrimethamine. Pyrimethamine is a folic acid antagonist whose main common side effect is dose-related bone marrow suppression. Folinic acid should be administered concomitantly and blood cell counts checked twice a week. An oral 200-mg loading dose is recommended followed by 50 (<60 kg) to 70 mg (>60 kg) per day orally. No intravenous form is available. Pyrimethamine should be combined with sulfadiazine or clindamycin. Sulfadiazine acts synergistically with pyrimethamine as a folic acid antagonist. Crystalluria and oliguria with renal failure should be prevented by hyperhydratation. Skin rash is the most common side effect and may be life threatening. Desensitization protocols have been successful in allergic patients who required sulfadiazine. The dosage is 1,000 mg (<60 kg) to 1,500 mg (>60 kg) orally every 6 h. No intravenous form is available. Clindamycin is an antibiotic that inhibits protein synthesis and seems to act by targeting translation in the T. gondii apicoplast. The main adverse reactions to clindamycin include rash, nausea, vomiting, and diarrhea, which may be associated with Clostridium difficile. Clindamycin can be administrated orally or intravenously. The dosage is 600 mg every 6 h by either route.

29.5.1 Possible Alternative Regimens Trimethoprim-sulfamethoxazole can be used as an alternative to pyrimethamine.

29  Parasitic Lung Infections

Other drugs such as atovaquone (1,500 mg orally twice a day), dapsone (100 mg orally once a day), azithromycin (900–1,200 mg once a day), or clarithromycin (500 mg every 12 h) can be used in combination with pyrimethamine. These combinations are less effective than pyrimethamine plus sulfadiazine or clindamycin.

29.5.2 Management of Pulmonary Toxoplasmosis in Hematopoietic Stem Cell Transplant Recipients Due to the diagnostic difficulties and considerable mortality related to disseminated toxoplasmosis, preemptive treatment must be initiated at symptom onset. Thus, PCR monitoring of T. gondii is extremely useful in these patients. In their review, Sing et al. [25] showed that about half the patients died within 3 days after pulmonary symptom onset. No data are available to determine the optimal drug combination for treating pulmonary toxoplasmosis. Extrapolating from previous experience supports the use of pyrimethamine plus sulfadiazine. In the most severe forms, if gastrointestinal absorption may be impaired, intravenous clindamycin should used instead of oral sulfadiazine. Adjunctive corticosteroid therapy needs further evaluation. The time to clinical response remains to be evaluated. The changes at the end of the first week are of crucial importance; ideally, the patient should be clinically improved, with negative PCT tests in blood and bronchoalveolar lavage fluid and fading of the radiographic infiltrates. The optimal treatment duration is unknown, and the drugs are often given for 6–8 weeks. After successful primary treatment, maintenance therapy or secondary prophylaxis is required with lower drug doses (half the initial dosage for pyrimethamine, sulfadiazine or clindamycin). The duration of the maintenance therapy depends on many factors, such as immune recovery of the patient, engraftment, graftversus-host-disease prevention or treatment with ­immunosuppressive drugs, and whether the immunosuppressive drug regimen was interrupted. After toxoplasmosis treatment, hematopoietic stem cell recipients should continue to receive suppressive doses of trimethoprim-sulfamethoxazole or an alternative regimen for the duration of their immunosuppression

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(bone-marrow transplant guidelines). Intolerance to the treatment is frequent and may lead to poor patient adherence to maintenance therapy.

29.5.3 Primary Prophylaxis Prophylaxis with trimethoprim-sulfamethoxazole has been proven effective against T. gondii reactivation in AIDS patients and can be used after ­allogeneic bone marrow transplantation. High trimethoprimsulfamethoxazole dosages may be more effective than low dosages [33]. In part because trimethoprimsulfamethoxazole may depress hematopoiesis, T. gondii prophylaxis is rarely used now in bone ­marrow transplant recipients, even those at highest risk, and there is no evidence to support such prophylaxis. Nevertheless, clinical observation shows that disseminated toxoplasmosis may develop in patients who do not receive chemoprophylaxis, in keeping with data on AIDS. Thus, routine chemoprophylaxis in high-risk patients may effectively prevent toxoplasmosis reactivation in bone marrow transplant recipients [34]. In practice, because reactivation of chronic infection is the most common cause of toxoplasmosis after allogeneic hematopoietic stem cell transplantation, patients who are seropositive should receive prophylaxis (Table  29.1). Post-transplantation serological testing is not helpful in this group of patients because the results may be affected by the use of intravenous immunoglobulins or by hypogammaglobulinemia. Therefore, pre-transplantation serological testing is crucial. Very few cases of toxoplasmosis related to transmission by the donor have been reported. Serological tests ensure the early diagnosis, allowing early preemptive therapy.

29.6 Strongyloidiasis All people infected with S. stercoralis should be treated to eradicate the infection. Three drugs are available, ivermectin, 200 mg/kg once daily; thiabendazole, 25 mg/kg twice daily; and albendazole, 400 mg twice daily.

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Table 29.1  Toxoplasmosis prophylaxis among seropositive allogeneic hematopoietic stem cell transplant (HSCT) recipients Indication First Choice Alternatives Prophylaxis among seropositive allogeneic HSCT recipients

Trimethoprim-sulfamethoxazole

Note: Start after engraftment and Adults/adolescents: administer as long as patients One double-strength (160/800 mg) tablet orally remain on immunosuppressive once daily; or therapy (i.e., generally, until 6 months after HSCT)

Clindamycin plus pyrimethamine plus leucovorin Adults/adolescents Clindamycin: 300–450 mg orally every 6–8 h; plus pyrimethamine: 25–75 mg orally once daily; plus leucovorin: 10–25 mg orally once daily

One single-strength (80/400 mg) tablet orally once daily; or One double-strength tablet orally three times/week Pediatrics:

Pediatrics:

150 mg trimethoprim/750 mg sulfamethoxazole/ m2/day by mouth with any of the following schedules: two divided doses three times/week on consecutive days; or a single dose orally three times/week on consecutive days; or two divided doses daily for 7 days; or two divided doses three times/week on alternate days

Clindamycin: 20–30 mg/kg/day by mouth, in four divided doses; plus pyrimethamine: 1 mg/kg orally daily; plus leucovorin: 5 mg orally every 3 days

29.6.1 Management of Hyperinfection or Disseminated Infection Ivermectin 200 mg/kg orally once a day is the most efficient drug. The treatment must be continued for at least 7 days until the larvae are no longer detected in stool, sputum, and urine. Broad-spectrum antibiotics with activity against enteric organisms should be given also. Paralytic ileus may impair the absorption of ivermectin, even after nasogastric tube administration. Subcutaneous injections of veterinary preparations have been successful, whereas oral therapy has failed. The combination of ivermectin and albendazole has been used successfully to treat disseminated strongy­ loidiasis. The treatment must be repeated if the infection is not eradicated (presence of larvae in stool 2 weeks after treatment completion).

29.6.2 Preventive Therapy Candidates for allogeneic or autologous hematopoietic stem cell transplantation should avoid contact with soil, beaches, or other surfaces that might be

contaminated by human feces. Health-care workers (in hospitals or institutions) should wear gloves when working with patients or in areas with possible fecal contamination.

29.6.3 Preventing Disease and Disease Recurrence Candidates for allogeneic hematopoietic stem cell transplantation or immunosuppressive chemotherapy should be screened for S. stercoralis using serological tests and eosinophil counts, especially those who have visited or lived in endemic areas or who have HTLV1 infection (which impairs the Th2 immune response). The same recommendations apply to autologous hematopoietic stem cell transplantation, although strongyloidiasis is rarely reported in association with this procedure. Empiric treatment with ivermectin (200 mg/kg/day orally for 2 consecutive days then repeat after 2 weeks) is required even if multiple stool examinations are negative. Alternative treatments consist of albendazole 400 mg orally twice daily for 7 days and thiabendazole 25 mg/kg (maximum 3 g/day) orally bid for 2 days. A

29  Parasitic Lung Infections

total of three stool examinations is required if the serologic tests are negative and strongyloidiasis is suspected clinically. To prevent recurrences, parasite clearance should be controlled by performing three or more stool examinations. Chemoprophylaxis is not recommended after hematopoietic stem cell transplantation to prevent strongyloidiasis recurrence, because data are lacking.

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b

29.6.4 Clinical Vignette 29.6.4.1 Disseminated Toxoplasmosis A 40-year-old women with a history of idiopathic medullary aplasia received an HLA-identical peripheral blood stem cell transplant on October 25 (day 0) after conditioning with fludarabine (52.5 mg), cyclophosphamide (3,720 mg), and anti-CD52 antibodies (30 mg) (chest X-ray A). She received cyclosporine and mycophenolate for prevention of graft-versus-host disease. The pretransplant IgG anti-T. gondii titer for toxoplasmosis was 8  IU/mL (positive if >7 IU/mL), with no IgM anti­ bodies. Aerosolized pentamidine was given for Pneumocystis pneumonia prophylaxis because of a

c

a

previous cutaneous reaction to sulfonamides. On day 18, her blood leukocyte count reached 2,000/mm3. On day 20, a fever developed and persisted despite broadspectrum antimicrobials. On day 22, she had a blood leukocyte count of only 500/mm3 with thrombocytopenia. A skin reaction consistent with graft-versus-host disease prompted intensification of the corticosteroid therapy. Cytomegalovirus antigenemia was positive (19 cells), and she was given the antiviral gancyclovir.

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The chest X-ray (B) was considered unchanged. A fever of 38°C persisted without any other findings except persistent cytomegalovirus antigenemia. On day 30, rapid onset of severe tachypnea and hypoxia required ICU admission and noninvasive mechanical ventilation. The chest X-ray (C) showed bilateral alveolar infiltrates. The echocardiogram disclosed a moderate pericardial effusion and diffuse hypokinesia. On day 31, she had two episodes of seizures and required intubation. All microbiological tests were negative. The Giemsa stain on bronchoalveolar lavage fluid was negative. A second bronchoalveolar lavage performed on day 42 because of clinical deterioration showed T. gondii tachyzoites. Retrospective PCR analysis of bronchoalveolar lavage fluid obtained on day 31 was positive. Tests for IgM antibodies were negative. Treatment with pyrimethamine and clindamycin was started, but the patient died on day 59 from multiple organ failure and fungal superinfection.

References   1. Duband S, Cornillon J, Tavernier E, Dumollard JM, Guyotat  D, Peoc’h M (2008) Toxoplasmosis with hemo­ phagocytic syndrome after bone marrow transplantation: diagnosis at autopsy. Transpl Infect Dis 10(5):372–374   2. Edvinsson B, Lappalainen M, Anttila VJ, Paetau A, Evengard B (2009) Toxoplasmosis in immunocompromised patients. Scand J Infect Dis 41(5):368–371   3. Roxby AC, Gottlieb GS, Limaye AP (2009) Strongyloidiasis in transplant patients. Clin Infect Dis 49(9):1411–1423   4. Wirk B, Wingard JR (2009) Strongyloides stercoralis hyperinfection in hematopoietic stem cell transplantation. Transpl Infect Dis 11(2):143–148   5. Darde ML (2008) Toxoplasma gondii, “new” genotypes and virulence. Parasite 15(3):366–371   6. Maubon D, Ajzenberg D, Brenier-Pinchart MP, Darde ML, Pelloux H (2008) What are the respective host and parasite contributions to toxoplasmosis? Trends Parasitol 24(7): 299–303   7. Ajzenberg D, Yera H, Marty P et al (2009) Genotype of 88 Toxoplasma gondii isolates associated with toxoplasmosis in immunocompromised patients and correlation with clinical findings. J Infect Dis 199(8):1155–1167   8. Fricker-Hidalgo H, Bulabois CE, Brenier-Pinchart MP et al (2009) Diagnosis of toxoplasmosis after allogeneic stem cell transplantation: results of DNA detection and serological techniques. Clin Infect Dis 48(2):e9–e15   9. Martino R, Bretagne S, Einsele H et al (2005) Early detection of Toxoplasma infection by molecular monitoring of

J.-F. Timsit et al. Toxoplasma gondii in peripheral blood samples after allogeneic stem cell transplantation. Clin Infect Dis 40(1): 67–78 10. Sugiyama K, Hasegawa Y, Nagasawa T, Hitomi S (2006) Exposure of medical staff to Strongyloides stercolaris from a patient with disseminated strongyloidiasis. J Infect Chemother 12(4):217–219 11. Siddiqui AA, Berk SL (2001) Diagnosis of Strongyloides stercoralis infection. Clin Infect Dis 33(7):1040–1047 12. Keiser PB, Nutman TB (2004) Strongyloides stercoralis in the immunocompromised population. Clin Microbiol Rev 17(1):208–217 13. Pomeroy C, Filice GA (1992) Pulmonary toxoplasmosis: a review. Clin Infect Dis 14(4):863–870 14. Rabaud C, May T, Lucet JC, Leport C, Ambroise-Thomas P, Canton P (1996) Pulmonary toxoplasmosis in patients infected with human immunodeficiency virus: a French National Survey. Clin Infect Dis 23(6):1249–1254 15. de Medeiros BC, de Medeiros CR, Werner B, Loddo G, Pasquini R, Bleggi-Torres LF (2001) Disseminated toxoplasmosis after bone marrow transplantation: report of 9 cases. Transpl Infect Dis 3(1):24–28 16. Derouin F, Pelloux H (2008) Prevention of toxoplasmo­sis in transplant patients. Clin Microbiol Infect 14(12): 1089–1101 17. Meers S, Lagrou K, Theunissen K et al (2010) Myeloablative conditioning predisposes patients for Toxoplasma gondii reactivation after allogeneic stem cell transplantation. Clin Infect Dis 50:1127–1134 18. Peleg AY, Husain S, Kwak EJ et  al (2007) Opportunistic infections in 547 organ transplant recipients receiving alemtuzumab, a humanized monoclonal CD-52 antibody. Clin Infect Dis 44(2):204–212 19. Martin SI, Marty FM, Fiumara K, Treon SP, Gribben JG, Baden LR (2006) Infectious complications associated with alemtuzumab use for lymphoproliferative disorders. Clin Infect Dis 43(1):16–24 20. Mele A, Paterson PJ, Prentice HG, Leoni P, Kibbler CC (2002) Toxoplasmosis in bone marrow transplantation: a report of two cases and systematic review of the literature. Bone Marrow Transplant 29(8):691–698 21. Escuissato DL, de Aguiar RO, Gasparetto EL, Muller NL (2004) Disseminated toxoplasmosis after bone marrow transplantation: high-resolution CT appearance. J Thorac Imaging 19(3):207–209 22. Montoya JG, Liesenfeld O (2004) Toxoplasmosis. Lancet 363(9425):1965–1976 23. Ortonne N, Ribaud P, Meignin V et al (2001) Toxoplasmic pneumonitis leading to fatal acute respiratory distress syndrome after engraftment in three bone marrow transplant recipients. Transplantation 72(11):1838–1840 24. Laibe S, Ranque S, Curtillet C, Faraut F, Dumon H, Franck J (2006) Timely diagnosis of disseminated toxoplasmosis by sputum examination. J Clin Microbiol 44(2):646–648 25. Sing A, Leitritz L, Roggenkamp A et al (1999) Pulmonary toxoplasmosis in bone marrow transplant recipients: report of two cases and review. Clin Infect Dis 29(2):429–433 26. Dulley FL, Costa S, Cosentino R, Gamba C, Saboya R (2009) Strongyloides stercoralis hyperinfection after allogeneic stem cell transplantation. Bone Marrow Transplant 43(9):741–742

29  Parasitic Lung Infections 27. Safdar A, Malathum K, Rodriguez SJ, Husni R, Rolston KV (2004) Strongyloidiasis in patients at a comprehensive cancer center in the United States. Cancer 100(7):1531–1536 28. Orlent H, Crawley C, Cwynarski K, Dina R, Apperley J (2003) Strongyloidiasis pre and post autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 32(1):115–117 29. Roman-Velez JM, Martinez-Camacho RN, Alayon-Laguer D et al (2009) An unusual presentation of alveolar hemorrhage. Prim Care Respir J 18(4):337–339 30. Schaffel R, Portugal R, Maiolino A, Nucci M (2004) Strongyloidiasis pre and post autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 33(1):117

367 31. ten Hove RJ, van Esbroeck M, Vervoort T, van den Ende J, van Lieshout L, Verweij JJ (2009) Molecular diagnostics of intestinal parasites in returning travellers. Eur J Clin Micro­ biol Infect Dis 28(9):1045–1053 32. Segarra-Newnham M (2007) Manifestations, diagnosis, and treatment of Strongyloides stercoralis infection. Ann Pharmacother 41(12):1992–2001 33. Roemer E, Blau IW, Basara N et al (2001) Toxoplasmosis, a severe complication in allogeneic hematopoietic stem cell transplantation: successful treatment strategies during a 5-year single-center experience. Clin Infect Dis 32(1):E1–8 34. Martino R, Cordonnier C (2003) Toxoplasmosis following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 31(7):617–618, author reply 9

 

Pulmonary Mycobacterial Infections in Patients with Hematological Malignancies

30

Khalid A. Al-Anazi and Asma M. Al-Jasser

Contents 30.1

Introduction............................................................. 369

30.2 Incidence and Risk Factors of Tuberculosis in Patients with Hematological Malignancies...... 369 30.3 Clinical Presentations of Tuberculosis in Patients with Hematological Malignancies...... 370 30.4 Diagnosis of Active Tuberculosis........................... 371 30.4.1 Clinical Manifestations............................................. 371 30.5 Outcomes and Treatment of Tuberculosis in Patients with Hematological Malignancies...... 374 30.5.1 Antituberculous Drug Therapy................................. 374 30.6

Multidrug Resistant Tuberculosis......................... 376

30.7 Latent Tuberculosis................................................ 376 30.7.1  Diagnosis of Latent Tuberculosis............................. 376 30.8 Nontuberculous Mycobacterial Infections........... 377 30.8.1 Diagnosis of NTM Nontuberculous Mycobacterial Infections.......................................... 377 30.9 Mycobacterial Infections in Stem-Cell Transplant Recipients............................................. 378

30.1  Introduction Patients with hematological malignancies are at increased risk for infection with Mycobacterium tuberculosis and nontuberculous mycobacteria (NTM), which usually (but not consistently) manifest as pulmonary disease [1, 4, 9, 21, 93, 98]. Tuberculosis (TB) may be either active or latent. Latent TB is clinically silent and is not contagious, but can undergo reactivation when the malignancy or treatment causes immunosuppression [23]. Patients should be evaluated and sometimes treated for latent TB infection when they are diagnosed with immunosuppressive conditions or before starting treatment with immunosuppressive agents such as corticosteroids or monoclonal antibodies [67]. Both TB and NTM infection may progress rapidly to severe disseminated disease in immunocompromised patients, making the early diagnosis crucial, as specific antimicrobial agents must be given [40, 47, 96, 107, 110].

References............................................................................ 379

30.2 Incidence and Risk Factors of Tuberculosis in Patients with Hematological Malignancies

K.A. Al-Anazi (*) Section of Adult Hematology and Hematopoietic Stem Cell Transplantation, Oncology Centre, King Fahad Specialist Hospital, P.O. Box 15215, Dammam 31444, Saudi Arabia e-mail: [email protected] A.M. Al-Jasser Central Laboratory, Ministry of Health, P.O. Box 61734, Riyadh 11575, Saudi Arabia e-mail: [email protected]

The incidence of mycobacterial infections in patients with hematological malignancies largely depends on the background incidence in the community and ranges from ninefold to 22-fold of that in the general population [10, 56, 97]. TB prevalence in these patients ranges from less than 1% to more than 10% [93]. Reactivation of latent TB is common and often causes severe disseminated disease [96]. When TB occurs as a complication of diagnosed hematological malignancies, the mean time from chemotherapy completion to development of

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_30, © Springer-Verlag Berlin Heidelberg 2011

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TB is 3–20 months [1, 4, 56]. TB does not usually delay chemotherapy and, once treated, rarely flares up during subsequent chemotherapy cycles [65]. Among hematological malignancies, acute leukemia has the strongest association with TB [56, 65]. A high index of suspicion should be maintained in patients with acute leukemia living in areas of TB endemicity [4, 97]. In adults, TB is more common in acute myeloid leukemia than in acute lymphoblastic leukemia, despite the use of steroids and radiotherapy to treat this disease. TB is also common in patients with hairy cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, multiple myeloma, Hodgkin’s and non-Hodgkin’s lymphoma, and myelodysplastic syndrome [1, 4, 38, 56, 64, 69, 93, 97]. Among lymphomas, nodular sclerotic Hodgkin’s disease has the strongest association with TB [62]. Tyrosine kinase inhibitors and monoclonal antibodies used to treat hematological malignancies have been associated with TB (Table 30.1) [9, 18]. In chronic TB, CD8+ T-cells assist macrophages in controlling the intracellular mycobacteria via a mechanism orchestrated by the T-cell receptor. The tyrosine kinase inhibitor imatinib affects T-cell receptor signal transduction, suggesting a mechanism by which imatinib might increase the risk of TB reactivation [18]. Also, in areas Table 30.1  Risk factors for mycobacterial infections in patients with hematologic malignancy 1. The primary disease causing reduced immunity; particularly in relapse 2.  Old age 3.  Cytotoxic chemotherapy 4.  Corticosteroid therapy 5.  Radiotherapy 6. Other immunosuppressive therapies, e.g., monoclonal antibodies, tyrosine kinase inhibitors, etc. 7. Other comorbidities, e.g., diabetes mellitus, malnutrition, weight loss, etc. 8.  Hematopoietic stem cell transplant:   (a) Graft-versus-host disease; acute and chronic   (b) T-cell depletion   (c) Matched unrelated allografts   (d) Total body irradiation and cyclophosphamide conditioning   (e) Bronchiolitis obliterans

K.A. Al-Anazi and A.M. Al-Jasser

of TB endemicity, patients scheduled to receive the monoclonal antibody alemtuzumab should undergo a careful initial evaluation to determine whether prophylactic anti-TB therapy is in order [9]. Identification of risk factors for TB may be useful for TB prevention and earlier TB diagnosis. Risk factors for TB in patients with hematological malignancies include malnutrition; age older than 50  years; corticosteroid therapy; cytotoxic agents, particularly fludarabine; radiotherapy, a history of active TB; and residing in an endemic area (Table  30.1) [4, 6, 93]. Intravenous cytotoxic chemotherapy is associated with earlier and more disseminated TB infection compared to oral cytotoxic chemotherapy [4]. Routine screening of patients for latent TB infection and exclusion of active disease prior to cancer chemotherapy initiation may be discussed in endemic areas [17, 67]. Prophylactic anti-TB treatment of patients with a history of TB should help to minimize the risk of TB reactivation [4, 10, 96]. Chemotherapy solutions may undergo contamination with the BCG when prepared under biosafety hoods also used to prepare BCG solutions for bladder cancer treatment [111].

30.3 Clinical Presentations of Tuberculosis in Patients with Hematological Malignancies Although the lungs are involved in 70–90% of TB cases in patients with hematological malignancies [1, 93], dissemination to other sites is common [19, 46, 69]. Disseminated TB with miliary lung densities and pleural effusions develops in 10–15% of patients [1, 44, 46]. Risk factors for disseminated TB include advanced age, female sex, immunosuppression, diabetes mellitus, and weight loss (Table  30.1) [29, 107]. Disseminated TB may produce a variety of nonspecific symptoms, such as fever of unknown origin, anorexia, malaise, weight loss, cough, night sweats, headache, neck stiffness, choroid tubercles, altered mental status, abdominal pain, and hepatosplenomegaly [29, 63, 69]. Therefore, a high index of suspicion should be maintained so that appropriate investigations are conducted promptly. Disseminated TB is curable provided the diagnosis is made early and the treatment initiated promptly [4, 29, 63, 69, 107]. Specific treatment of macrophage activation syndrome may help to prevent associated organ

30  Pulmonary Mycobacterial Infections in Patients with Hematological Malignancies

dysfunction. In patients with advanced hematological malignancies, 27% of cases of disseminated TB are diagnosed at autopsy [29]. Pulmonary TB may manifest as TB pneumonia or cavitation. In a study in hematopoietic stem cell transplant (HSCT) recipients, the most common presenting symptom was a fever in TB pneumonia and hemoptysis in TB cavitation. Cavitation was often located in the upper lobes and diagnosed early, whereas TB pneumonia was randomly distributed and often diagnosed late [54]. TB infection shares similar clinical and radiological features to those seen in infections due to NTM [10].

30.4  Diagnosis of Active Tuberculosis 30.4.1  Clinical Manifestations The early diagnosis of TB is particularly important in patients with hematological malignancies, given the high risk of severe and rapidly progressive disseminated disease [107]. Careful attention should be given to clinical symptoms such as persistent cough, pyrexia, night sweats, dyspnea, hemoptysis, or chest pain [41, 42, 93]. However, these symptoms are not specific and may overlap with those of the hematological malignancy, and the immunodeficiency may attenuate the symptoms of TB. Therefore, a high level of suspicion is crucial [2, 19, 93, 97].

30.4.1.1  First-Line Investigations Sputum smear examination is the mainstay of the diagnosis of pulmonary TB, but is often negative in immunocompromised patients. Furthermore, staining does not differentiate M. tuberculosis from NTMs [90, 100]. Once TB is suspected, a chest radiograph should be obtained [19]. Findings vary widely and may include areas of consolidation consistent with pneumonia, fine reticulonodular shadows consistent with pulmonary fibrosis, calcification, pleural effusions, lymph node enlargement, basal atelectasis, cavity formation, and miliary shadows (Figs. 30.1, 30.2 and 30.4). However, the chest radiograph is normal in a substantial proportion of patients [4, 44, 63, 69, 102].

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Routine laboratory tests may show a variety of abnormalities. Anemia is common and is usually mild and responsive to anti-TB treatment, although a hemolytic or immune mechanism may be involved [55, 72, 94]. Other hematological abnormalities may include leukocytosis, neutrophilia, lymphocytosis, lymphocytopenia, monocytosis, monocytopenia, thrombocytosis, and thrombocytopenia [4, 55, 66, 70, 94]. Immune thrombocytopenic purpura, thrombotic thrombocytopenic purpura, and hemophagocytic syndrome have been reported [72, 106]. Hematological abnormalities may be associated with a poor prognosis [35, 37]. Other abnormalities reported in patients with TB and possibly mediated by macrophage activation syndrome include elevated erythrocyte sedimentation rate; high serum levels of ferritin, vitamin B12, alkaline phosphatase, and lactic dehydrogenase; low serum levels of albumin, sodium, and calcium; hypoxemia; and hyponatremia. Another possible feature is liver dysfunction, mainly in the form of hepatic transaminase elevation [29, 37, 58, 63, 69, 70, 109]. The tuberculin skin test (TST) may be positive in about one-third of cases, although this may indicate infection with other mycobacterial species or vaccination with the BCG [18, 63]. Two interferon-gamma release assays (IGRAs) intended for use on blood samples have emerged as alternatives to the TST [13, 52, 82]. In patients with TB, interferon-gamma [INF-g] is released from T-cells after stimulation with specific TB antigens (ESAT-6 and CFP-10) that are highly specific for M. tuberculosis but absent from the BCG and most NTMs [13, 19, 52, 81, 82]. A positive result indicates a cellular immune response to M. tuberculosis. Although IGRAs were designed to detect latent TB, they may assist in the diagnosis of active TB in immunocompromised individuals. However, a negative result does not rule out active TB [19].

30.4.1.2  Other Investigations CT of the chest may rapidly provide valuable clues to the diagnosis of TB and allows an accurate assessment of the extent, pattern, and sites of TB infection, and provides information on complications such as cavities, bronchogenic spread, bronchiectasis, and aspergillomas (Fig.  30.2) [51, 102]. Serial CT scans are helpful in monitoring disease progression [51]. However, CT of the lung may lack

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K.A. Al-Anazi and A.M. Al-Jasser

c

b

Fig. 30.1  (a) Bilateral hilar lymphadenopathy and scarring of upper lobe of left lung. (b) Tuberculous consolidation involving right upper lobe. (c) Cavitation of upper lobe of the right lung

due to tuberculosis. Figure  30.1 shows various radiological appearances of pulmonary tuberculosis

accuracy in febrile immunocompromised patients because of the absence of the typical cavitary consolidations of TB [22]. On positron emission tomography (PET) scans, pulmonary tuberculomas are commonly visible as foci of increased uptake. Therefore, in regions of TB endemicity, positive PET scan results may indicate TB rather than lung involvement by the malignancy [32]. In patients with pulmonary TB, cultures of sputum and bronchoalveolar lavage (BAL) fluid may recover

the organism. BAL is a good alternative to more invasive investigations that are risky in these frail patients [15, 73]. When the infection is disseminated, blood and bone marrow cultures may be positive, and histological examination of biopsies from lymph nodes, bone marrow, and/or the liver may show the organism and/or granulomas [63, 69]. Thus, bone marrow examination usually shows decreased iron stores, histiomonocytosis, granulomas without giant cells, a positive Ziehl–Neelsen stain, and positive cultures (Fig. 30.3) [35, 58, 63, 69].

30  Pulmonary Mycobacterial Infections in Patients with Hematological Malignancies

373

a

b Fig. 30.4  Shows an Aspergillus ball in a tuberculous cavity on a chest X-ray

Fig. 30.2  (a) CAT scan showing upper lobe consolidation and a solitary nodule. (b) CAT scan of lungs showing diffuse miliary micronodular shadows. Figure  30.2 shows various CAT scan appearances in pulmonary tuberculosis

Axial mediastinoscopy may deserve consideration in selected patients with lesions in the axial medias­ tinum, given its good yield, low cost, and few contra­ indications. A large retrospective study of axial mediastinoscopy in patients with various mediastinal lesions, including TB and lymphoma, showed that global sensitivity, global specificity, accuracy, and mortality were 94%, 100%, 95%, and 0.0%, respectively [80]. Recent studies have shown that elevated CA-125 levels are found in several infections, including TB. The CA-125 level can serve as a marker of the ­treatment response and as an indicator of disease activity [113].

30.4.1.3  New Tests for Tuberculosis

Fig.  30.3  Shows Ziehl-Nelsen stain for acid-fast bacilli on a lung biopsy specimen

Many tests for TB have low sensitivity and specificity, and cultures require at least 3 weeks to become positive. Therefore, the development of new rapid tests has generated considerable interest. New versions of nucleic acid amplification (NAA) assays, immunebased assays, a skin patch test, and rapid culture systems have been introduced [76]. NAA assays are 80% sensitive but are highly specific, particularly with respiratory specimens [19]. Their sensitivity is too low and too variable to rule out TB in the event of a

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negative result, especially in paucibacillary disease with negative smears [30, 57, 74]. Nested PCRrestriction fragment length polymorphism analysis focusing on the hsp 65 gene performed well on 204 smear-positive and culture-positive sputum specimens [114]. The new molecular techniques are expected to complement rather than to replace conventional diagnostic tools. Further studies are needed to assess performance and to standardize assay procedures. Then guidelines will have to be developed on how best to use the new tools. Cost-effectiveness and economic constraints will have to be evaluated, particularly in low-income countries [100]. Serological (antibody-mediated) tests have been available for many years, although no guidelines recommend their use for diagnosing TB [19]. Published data on commercial serological tests provide inconsistent estimates of sensitivity and specificity. Combinations of carefully selected peptides derived from highly immunogenic proteins are being evaluated for use in immunodiagnostic tests for TB [90]. New tests are being developed for use in the laboratory. For instance, nucleic acid probes can be used to identify cultured organisms. Several new tests assist in detecting drug resistance [77, 100].

30.4.1.4  Therapeutic Trial Despite recent improvements in clinical and laboratory methods, the diagnosis of mycobacterial infections may still take weeks [10]. Microbiological studies may be negative in one-half to three-fourths of patients, and histological specimens may fail to show acid-fast bacilli (AFB) and typical epithelioidcell granulomas with caseation necrosis [4, 19, 46, 62]. Thus, many patients receive a presumptive diagnosis of TB based on the clinical and radiological manifestations. In this situation, a trial of anti-TB therapy may be justified [19, 41]. In patients with TB, the response to anti-TB medications is usually prompt and dramatic despite the immune system suppression [4, 38, 41, 46, 62, 65, 97]. If no clinical or radiological improvement is achieved within 2  months, the use of empirical therapy should be reevaluated [19].

K.A. Al-Anazi and A.M. Al-Jasser

30.5 Outcomes and Treatment of Tuberculosis in Patients with Hematological Malignancies 30.5.1  Antituberculous Drug Therapy 30.5.1.1  Antituberculous Drugs Early appropriate anti-TB treatment is effective [76]. However, a fatal outcome has been reported in 5%–10% of cases, and in patients who are diagnosed late and who have disseminated TB the mortality rate may reach 62.5% [2, 4, 46, 62, 65, 93]. Attributable mortality of TB in patients with hematological malignancies has ranged from 21% to 62.5% [4, 21, 93]. Postmortem examinations in these patients should include bacteriological and histological studies to establish the correct diagnosis [84]. The standard short-course therapy for TB recommended by the World Health Organization (WHO) is based on a four-drug regimen that must be strictly followed to prevent the acquisition of drug resistance. Direct observation of patient compliance is provided to ensure effective treatment. M. tuberculosis mutants resistant to any single drug are naturally present in any large bacterial population, irrespective of exposure to drugs. The frequency of mutants resistant to rifampin and INH is relatively high, and therefore the large extracellular population of actively metabolizing and rapidly growing tubercle bacilli in cavitary lesions contains organisms that are resistant to a single drug. The concomitant administration of multiple drugs is consequently crucial to avoid selecting drug-resistant mutants [24]. Immunocompromised patients with TB should be treated for 9–12 months with INH and rifampin combined initially with ethambutol, streptomycin, or pyrazinamide [4, 95]. However, the treatment may need to be prolonged if the response is slow, and patients should be followed up carefully after the treatment to detect early relapses [95]. The current resurgence of TB, which is mainly ascribable to the development of multidrug resistant (MDR) and extensively drug-resistant (XDR) strains, has increased the need for studies into the molecular mechanisms of drug effects and drug resistance,

30  Pulmonary Mycobacterial Infections in Patients with Hematological Malignancies

which should provide valuable information for developing new compounds [24]. Unfortunately, since the introduction of rifampin 40 years ago, only two antiTB drugs have been marketed, rifabutin and rifapentine [104]. Nonclinical and clinical studies are focusing on the development of new and faster-acting anti-TB compounds, e.g., moxifloxacin, nitroimidazole, oxazolidinones, diarylquinoline, and rifamycin derivatives [104, 105]. Unfortunately, the development of adjuvant immunotherapy for TB is not progressing [104].

30.5.1.2  Compliance and Tolerance Noncompliance with anti-TB treatment regimens increases morbidity and mortality rates, perpetuates transmission, and generates bacterial resistance. Data on the incidence and risk factors of noncompliance are needed to design interventions. Risk factors for noncompliance include treatment required for more than 2  months, low socioeconomic status, age between 21 and 30 years, and a history of skipping more than two doses. Direct observation of treatment may be needed to ensure adequate compliance. Another strategy consists of providing support to the family and intervening immediately in the event of missed doses [12]. Although M. tuberculosis is eradicated rapidly during therapy in some patients with pulmonary TB, it may persist for many months in others. Tolerance to anti-TB medications emerges after prolonged drug exposure and may be an important determinant of the outcome of TB therapy [112].

30.5.1.3  Side Effects Major adverse reactions to anti-TB drugs can cause significant morbidity and limit the use of anti-TB medications. Risk factors include female sex, age older than 60 years, and birthplace in Asia [116]. The incidence of major side effects from first-line anti-TB agents was highest with pyrazinamide and lowest with ethambutol. More specifically, the rates of hepatotoxicity and rash were substantially higher with pyrazinamide than with other first-line anti-TB drugs and higher than previously reported [116].

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Anti-TB drug-induced hepatotoxicity is not uncommon and is significantly more frequent in patients with pre-existing liver disease, low basal metabolic index, and extensive or open pulmonary TB. Early diagnosis and treatment is crucial, particularly in developing countries where both TB and liver disease are common [60]. INH-induced hepatitis is uncommon, but when it occurs it resolves completely if the drug is stopped early enough. Fatal forms of hepatitis are extremely rare if the patients are monitored closely. The overall mortality rate from INH hepatotoxicity is less than 0.01% [17, 88]. Agranulocytosis (pancytopenia) has been reported in patients receiving anti-TB treatment. It usually develops 1–3  months after starting treatment and is allergic in nature [92]. Leukopenia may develop during anti-TB treatment, but does not require immediate treatment discontinuation, as the leukocyte count recovers spontaneously or remains stable during treatment in most instances. Patients who develop leukopenia due to anti-TB drugs may have weaker natural or acquired immunological responses to TB infection and greater vulnerability of bone marrow and hepatic cells to anti-TB agents [68].

30.5.1.4  Corticosteroid Therapy Patients with hematological malignancies often receive corticosteroid therapy as part of their anticancer regimen [14]. In patients with TB infection, corticosteroid therapy is indicated in some forms of extrapulmonary disease such as pleurisy, meningitis, pericarditis, and adrenal gland infection. Other indications include endobronchial disease, hypersensitivity reactions to drugs or infection, and severe systemic manifestations due to pulmonary or extrapulmonary infection [7, 14, 28]. The usual prednisone dose is 40–60 mg/day orally for 4–6  weeks depending on the system involved, after which the dose is tapered gradually [7]. Randomized, placebo-controlled studies are required to determine the role for corticosteroids in the standard therapy of TB [7, 14]. Corticosteroids may interact with other medications, e.g., oral contraceptives and rifampin [7].

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30.5.1.5  Surgery In patients with malignant hematological disorders and tuberculomas or localized tuberculous pulmonary cavitations, surgical resection of the involved segment or lobe may be essential not only to eradicate pulmonary TB, especially if the infection is caused by an MDR organism, but also to prevent the development of further complications such as aspergilloma (Fig. 30.3) after further immune depression occurs due to disease progression or cytotoxic chemotherapy [6, 99, 101].

30.6  Multidrug Resistant Tuberculosis The emergence of MDR-TB and, more recently, of XDR-TB is a major threat to TB control and eradication. The prevalences of MDR-TB and XDR-TB are inversely proportional to the quality of TB control and of second-line anti-TB drug utilization [61]. For some MDR-TB and XDR-TB strains, no curative treatment is available. Concern that these strains may spread around the world is prompting active research into new diagnostic tools, anti-TB drugs, and TB vaccines [77]. The risk of uncontrollable MDR-TB and XDR-TB outbreaks is real considering the current levels of financing and commitment to care [61]. Global risk factors for MDR-TB include a history of anti-TB treatment and a known contact with a person having drugresistant TB [33]. Traditional laboratory methods for detecting drug resistance are slow and not generally available outside specialized laboratories [33]. Rapid molecular methods are increasingly used in well-resourced settings, and simple cheap alternatives are being developed for resource-limited settings [33, 64]. Line-probe assays, bacteriophage-based assays, molecular beacons, and the microscopic-observation drug-susceptibility assay can assist in detecting drug resistance [76, 77, 100]. The prevention of drug-resistant TB rests on optimizing compliance with anti-TB therapy and promptly detecting resistant strains [33]. Few data are available to guide the drug treatment of resistant TB. Well-designed regimens based largely on second-line anti-TB drugs can considerably improve cure rates [61]. However, new drugs free of crossresistance with known antimycobacterial agents are urgently needed [105].

K.A. Al-Anazi and A.M. Al-Jasser

30.7  Latent Tuberculosis 30.7.1  Diagnosis of Latent Tuberculosis Identifying and treating patients with latent TB infection are crucial to prevent reactivation [23, 81]. Until recently, the diagnosis of latent TB infection relied solely on the century-old TST, which has a number of limitations [13, 52]. In immunocompromised individuals, an induration of 5 mm or more is considered positive [17, 67]. The TST results may be falsely negative due to drug therapy or to anergy related to the malignancy [17]. Two-step testing may increase the TST yield [67]. The introduction of two IGRAs (T-SPOT. TB and QuantiFERON-TB gold) is a major advance [13, 52, 67, 82]. Immunosuppression does not affect the performance of these tests, which can identify a large proportion of TB-infected patients with anergy to tuberculin [13, 19, 49, 52, 67, 75, 79, 81, 82]. However, the QuantiFERON-TB gold test may produce negative or indeterminate results in immunocompromised patients [49]. IGRAs may be particularly helpful in regions where widespread BCG vaccination limits the usefulness of the TST [13, 19, 49, 52, 67, 75, 79, 81, 82]. IGRAs may decrease the unnecessary use of antiTB drugs in patients with positive TSTs because of BCG vaccination [52, 75]. The Canadian Tuberculosis Committee on IGRAs for diagnosing latent TB infection in immunocompromised individuals has issued the following recommendations: (1) TST should be used first; (2) if the TST is positive, a diagnosis of latent TB infection is given; (3) if the TST is negative and the clinician is still concerned about the possibility of latent TB infection, an IGRA test may be performed; (4) if the IGRA result is positive, the person may be considered to have latent TB infection; and (5) if the IGRA result is indeterminate, the test should be repeated to rule out laboratory error [13].

30.7.1.1 Tuberculosis Chemoprophylaxis in Patients with Hematological Malignancies Immunosuppressive therapy and leukemia increase the risk of progression to active TB. INH chemoprophylaxis has been recommended in some groups of

30  Pulmonary Mycobacterial Infections in Patients with Hematological Malignancies

immunocompromised patients, including patients with hematological malignancies and/or iatrogenic immunosuppression. The usual dosage is 300  mg/day for 6–12 months [17, 71, 88, 115]. Patients with evidence of latent TB who require prolonged high-dose corticosteroid therapy (more than 10 mg/day of prednisolone) should receive chemoprophylaxis [115]. New guidelines recommend INH treatment for 6–9 months or rifampin for 4 months or with rifampin plus pyrazinamide for 2 months [17].

30.8 Nontuberculous Mycobacterial Infections 30.8.1 Diagnosis of NTM Nontuberculous Mycobacterial Infections NTM infection is not a communicable disease, although health care-associated outbreaks have been reported. M. avium complex (MAC) is the main NTM responsible for disease in humans [78, 103]. Lung involvement with a chronic productive cough, dyspnea, and hemoptysis is the most common presentation, although any organ can be affected [78]. NTMs are often difficult to identify, but repeated culturing of various sources including bone marrow may help to establish the diagnosis early [40]. When cultures are negative but serum alkaline phosphatase is elevated, a liver biopsy should be considered. Early diagnosis and prompt therapy are important, as NTM infection in patients with hematological malignancies may manifest as severe disseminated disease. Among hematological malignancies, hairy cell leukemia and chronic myelogenous leukemia may predispose patients more particularly to disseminated NTM infection [36, 47, 110]. NTM infection may be difficult to differentiate from colonization. Treatment of NTM pulmonary infection requires 18–24  months of treatment with multiple drugs selected based on the infecting species. This drug treatment is expensive, frequently noncurative, and associated with substantial side effects. Therefore, it is warranted only in patients with sufficient NTM-related pathology. The likelihood of infection as opposed to colonization is greater in patients receiving intensive cytotoxic chemotherapy and in

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those with previous pulmonary involvement by the malignancy. Clinicians must cooperate with microbiologists, pathologists, and radiologists to improve treatment outcomes [50, 78, 83]. M. kansasii may cause pulmonary or disseminated infection in patients with hematological malignancies. A single isolation of the organism may not be clinically significant, and the diagnosis can only be established after a second isolation unless the clinical situation strongly supports infection. Lung cavitation is the main radiological presentation [25, 27]. In a study of 12 patients with the slow-growing NTM M. lentiflavum, 11 (92%) patients had a hematological malignancy [86]. However, slow-growing NTMs are very rarely a probable cause of infection. Risk factors for infections due to slow-growing mycobacteria are severe lymphocytopenia, systemic steroids, and acute graft-versus-host disease (GvHD) in hematopoietic stem-cell transplant (HSCT) recipients (Table  30.1) [86]. Rapidly growing mycobacteria cause colonization about eight times more often than they cause true infection. Nevertheless, infection with these organisms should be considered in patients with pulmonary infiltrates, particularly those treated with intensive chemotherapeutic regimens [83].

30.8.1.1 Treatment of Nontuberculous Mycobacterial Infections NTM infections are usually difficult to treat, as they do not respond to traditional anti-TB agents. At least three effective drugs are usually required for at least 12  months after sputum cultures become negative [50, 78]. Novel antimicrobial agents including clarithromycin and azithromycin were effective in three pediatric patients with acute lymphoblastic leukemia and NTM infection [98]. The new macrolides have shown limited effectiveness in patients with MAC disease [87]. Patients with macrolide-resistant MAC isolates have higher mortality rates than patients with macrolide-susceptible isolates. Since the advent of the new macrolides, no substantial progress has been made in the treatment of MAC lung disease or NTM infections in general. Firstline treatment offers the best opportunity for a cure, and protection against the emergence of macrolideresistant MAC isolates is crucial [34]. MAC isolates are usually susceptible to clofazidime, cycloserine,

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and ansamycin and resistant to isoniazid, streptomycin, ethambutol, rifampin, and ethionamide [47]. The pulmonary diseases caused by certain types of NTM such as M. kansasii or M. szulgai are usually treated with rifampin, ethambutol, and isoniazid, i.e., the same regimens that generally lead to satisfactory results in patients with TB [87]. Although rifampinbased conventional and combined chemotherapy is usually effective in the treatment of M. kansasii infections, persistence and recurrence develop in 11% and 7% of patients, respectively [25, 27, 43]. On the other hand, M. lentiflavum is usually susceptible to isoniazid, ethambutol, clarithromycin, and amikacin, but resistant to rifampin [87]. In patients infected with NTM, the main indications for surgical resection are continuous hemoptysis, continuous productive cough, exacerbation of CXR ­features, and localized disease that fails medical management [78, 87].

30.9 Mycobacterial Infections in Stem-Cell Transplant Recipients Cell-mediated immunity is severely impaired in allogeneic HSCT recipients due to pre-transplant conditioning regimens, immunosuppressive therapy, and GvHD. These patients have a 10- to 40-fold increase in the mycobacterial infection rate compared to the general population [11, 20, 26, 48]. The incidence of mycobacterial infections varies considerably according to the type of HSCT, type of infective mycobacteria, and incidence in the local general population [3–5, 8, 16, 20, 21, 26, 39, 53, 91, 117]. In allogeneic HSCT recipients, it ranges from 0.49% to 9.7% [4, 5, 11, 16, 21, 26, 31, 39, 53, 59, 85]. The incidence of NTM infections in allogeneic HSCT recipients is approximately 1.9% [8]. Among allogeneic HSCT recipients, those with acute or chronic myelogenous leukemia or myelodysplastic syndrome are at highest risk for mycobacterial infections. Other risk factors include the use of total body irradiation, cyclophosphamide, and busulphan in the conditioning regimen; acute or chronic extensive GvHD; corticosteroid therapy; T-cell depletion in allografts; mismatched allografts or matched unrelated donor grafts; and previous history of TB infection (Table 30.1) [4, 5, 16, 20, 26, 39, 53]. Factors selectively associated with

K.A. Al-Anazi and A.M. Al-Jasser

NTM infections in HSCT recipients include leukemia relapse, mismatched allografts or matched unrelated donor grafts, acute GvHD, and bronchiolitis obliterans (Table 30.1) [8]. Mycobacterial infections develop within 45–365 days after allograft transplantation [4, 5, 11, 16, 20, 39, 53, 59]. The lungs are involved in 50%–100% of patients [4, 5, 8, 11, 20, 39]. Clinical manifestations include unexplained pyrexia, cough, dyspnea, and pleuritic chest pain. Imaging studies may show air-space consolidation, diffuse reticulonodular shadows predominating in the upper lobe, tree-in-bud appearance, ground-glass opacities, cavity formation, and hilar and mediastinal lymphadenopathy (Figs. 30.1, 30.2 and 30.4). In the absence of prompt treatment, rapid dissemination may occur, with severe pyrexia, adult respiratory distress syndrome (ARDS), hypotension, hypoxia, sepsis, multiorgan failure, and death [4, 16, 20, 21, 39, 48, 85, 91, 108]. Furthermore, dissemination with prominent extrapulmonary manifestations is a feature at presentation in at least one-third of cases [4, 21, 31, 48, 53, 59, 91]. Osteomyelitis and central venous catheter or tunnel infections have been reported in HSCT recipients with NTM infection [85]. The NTMs most often responsible for infections in HSCT recipients are M. fortuitum, M. chelonae, M. gordonnae, M. scrofolaceum, and M. avium intracellular [8]. Positive microbiological studies for NTM indicate severe immunosuppression and a poor prognosis. NTM may coexist with other pathogens such as Aspergillus. Colonization may be difficult to distinguish from infection, despite the development of elaborate but empirical clinical, radiological, and microbiological criteria. The threshold for starting therapy is unclear. However, invasive NTM infections require prolonged therapy [8]. In umbilical cord blood transplant (UCBT) recipients, mycobacterial infections may develop as early as day 45 after transplantation [59]. The risk is greatest in patients with acute myelogenous leukemia, mismatched grafts, T-cell depletion, GvHD, and residence in an area of TB endemicity (Table  30.1). Patients present with pyrexia, a cough, chest pain, and evidence of pneumonia [21, 91]. UCBT recipients may have higher incidences of disseminated mycobacterial infections and reactivation of previous mycobacterial MTB infection compared to other allogeneic HSCT recipients. Lung lesion histology usually shows caseous necrosis without granuloma

30  Pulmonary Mycobacterial Infections in Patients with Hematological Malignancies

formation. Combination anti-TB drug therapy is usually of limited efficacy [59]. The diagnosis of mycobacterial infections is challenging in HSCT recipients, who often have mild nonspecific symptoms and no granulomas in histological specimens [21]. In HSCT recipients with diffuse reticulonodular shadows, miliary TB should be suspected, as open lung biopsy shows this condition in 9% of cases. Respiratory failure and acute GvHD are the main events of adverse prognostic significance, and mortality may reach 50% in these patients [45]. Mycobacterial infections in HSCT recipients usually respond well to anti-TB treatment, particularly if the diagnosis is made early [4, 20]. The response rate may reach 90–100% with early treatment, compared to 50% or less when treatment is delayed [4, 20, 89, 107]. No excessive side effects of anti-TB medications have been reported [4, 39]. However, TB in HSCT recipients may complicate the post-transplant management, as anti-TB drugs frequently decrease the serum levels of cyclosporine-A, thus worsening GvHD [20]. INH prophylaxis has been used successfully to prevent TB reactivation in HSCT recipients [4]. However, the possible benefits of routine TB chemoprophylaxis in patients with positive TST results and normal CXR findings should be balanced against the risk of hepatotoxicity in HSCT recipients [5]. Therefore, INH prophylaxis should not be given routinely, but close follow-up and monitoring for reactivation of latent infection are recommended [16]. In patients who have received BCG immunotherapy and in those with inadequately treated TB, a TST should be performed and, when this test is positive, TB chemoprophylaxis should be considered [5]. Furthermore, in countries where TB is endemic, tests for latent TB should be performed before transplantation, chemoprophylaxis considered, and follow-up provided after transplantation [11].

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Part Noninfectious Pulmonary Involvement in Patients with HM

V

 

Pleuropulmonary Changes Induced by Drugs in Patients with Hematologic Diseases

31

Philippe Camus

Contents 31.1 Introduction......................................................... 387 31.2 Diagnostic Criteria for Drug-Induced Respiratory Disease............................................. 389 31.3 Patterns of Reactions to Drugs and Radiation....................................................... 390 31.3.1 Interstitial-Infiltrative Lung Diseases (ILD).......... 390 31.3.2 Pulmonary Nodules............................................... 396 31.3.3 Acute Chest Pain................................................... 396 31.3.4 Bronchospasm....................................................... 396 31.3.5 Pleural Involvement............................................... 397 31.3.6 Late Changes......................................................... 397 31.3.7 Drug-Induced Lymphoma and Second Cancers......... 397 31.4 Drugs Causing Pleuropulmonary Toxicity in Hematology...................................................... 398 31.4.1 Amphotericin B..................................................... 398 31.4.2 Anti-thymocyte Globulin....................................... 398 31.4.3 All-trans-Retinoic Acid (ATRA) and Arsenic Trioxide As2O3................................................ 398 31.4.4 Azacytidine............................................................ 399 31.4.5 Bis-Chlororethyl Nitrosourea Carmustine............. 399 31.4.6 Bleomycin............................................................. 399 31.4.7 Blood and Blood Products: Transfusion-Related Acute Lung Injury................................................. 401 31.4.8 Bortezomib............................................................ 403 31.4.9 Busulfan (Myleran)............................................... 403 31.4.10 Chlorambucil......................................................... 403 31.4.11 Colony-Stimulating Factors................................... 403 31.4.12 Corticosteroids....................................................... 404 31.4.13 Cyclophosphamide................................................ 404 31.4.14 Cytosine-Arabinoside (Ara-C).............................. 404 31.4.15 Dasatinib................................................................ 404 31.4.16 Deferoxamine........................................................ 405

P. Camus  Department of Pulmonary Disease and Intensive Care, University Medical Center Le Bocage & Medical School at the Université de Bourgogne, F-21079, Dijon, France e-mail: [email protected], [email protected], www.pneumotox.com

31.4.17 Etoposide............................................................... 405 31.4.18 Fludarabine............................................................ 405 31.4.19 Gemcitabine........................................................... 406 31.4.20 Hydroxyurea.......................................................... 406 31.4.21 Interferon............................................................... 406 31.4.22 Imatinib................................................................. 407 31.4.23 Lenalidomide......................................................... 407 31.4.24 Melphalan.............................................................. 407 31.4.25 Methotrexate.......................................................... 408 31.4.26 Procarbazine.......................................................... 409 31.4.27 Rituximab.............................................................. 409 31.4.28 Thalidomide........................................................... 410 31.4.29 Vinca Alkaloids..................................................... 410 31.5 Adverse Effects of Radiation Therapy to the Chest........................................................... 410 References............................................................................ 411

31.1 Introduction Patients with hematologic diseases who are being treated with therapy drugs, or receive radiation therapy or blood transfusions may develop a host of potentially fatal infectious and noninfectious pulmonary complications [1]. The increased complexity of multimodality and high-dose treatment regimens with the intended benefit of augmented antineoplastic efficacy and prolonged disease-free survival, the use of a panel of novel drugs to treat malignant and nonmalignant hematologic conditions (e.g., azacytidine, bortezomib, cladribine, dasatinib, fludarabine, imatinib, lenalidomide, rituximab, and thalidomide), total body irradiation (TBI) and hematopietic stem cell transplantation (HSCT) have increased the incidence of severe sometimes life-threatening pulmonary complications. As the incidence of infectious complications has decreased as a result of improved diagnostic methods

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_31, © Springer-Verlag Berlin Heidelberg 2011

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and effective prophylaxis, noninfectious, iatrogenic radiation- and drug-induced pulmonary complications have emerged as a major cause of early and late pulmonary morbidity, which may claim the lives of longterm survivors of hematologic malignancies. Toxic pneumonitis may account for 16% of all pulmonary events in this setting [2], and long-term adverse effects of treatments require prolonged follow-up in regard to the development of nonneoplastic and neoplastic conditions in heart and lung [3]. Noninfectious pulmonary complications represent a real challenge to the practitioner who needs be wary of the multitude of drug-, radiation- and procedure-induced adverse effects. Drug-induced respiratory disease in hematology patients may manifest acutely or subacutely by hypersensitivity reactions (bronchospasm, anaphylaxis), pulmonary edema, acute lung injury (ALI), an adult respiratory distress syndrome (ARDS) picture, diffuse alveolar hemorrhage, interstitial lung disease (ILD) with or without tissue eosinophilia, pleural effusion or pulmonary vasculopathy. The diagnosis of iatrogenic disease is complex, and it is by exclusion. The diagnosis is made against [1] pulmonary involvement from the underlying benign (e.g., sickle cell disease, myelodysplastic syndrome, polycythemia vera) or malignant hematologic condition (e.g., acute and chronic leukemias, Hodgkin’s and non-Hodgkin’s lymphoma, multiple myeloma), [2] alveolar hemorrhage, [3] circulatory overload, left ventricular dysfunction and [4] an opportunistic viral, bacterial, fungal or protozoan infection with few reliable clinical or imaging discriminators to separate these entities. To complicate matters, there is often little time for establishing the diagnosis and initiating appropriate therapy before the patient’s condition deteriorates irreversibly. Patients who require mechanical ventilatory support have an ominous outcome. There is almost no specific pattern of drug-induced lung involvement on pathology. Thus, the lung biopsy is mainly used to rule out diagnoses other than drugs, and patients suspected of having drug-induced lung disease may be managed conservatively using bronchoalveolar lavage (BAL), transbronchial lung biopsy (TBLB) and microbiological tests as the main diagnostic tools. Drug discontinuance followed by resolution of symptoms is a simple test that may aid in the recognition of drug-induced disease. The diagnosis of DIRD can be straightforward in patients with a benign underlying hematologic

P. Camus

condition who are being treated with a compatible drug as a solo agent, and drug discontinuance is followed by remission of symptoms. Drug-induced disease is more complex to diagnose in patients with a background of hematologic malignancy who received several potentially pneumotoxic drugs, each having different times for drug-induced disease to present, and/or who have received radiation therapy, blood transfusions or have a history of exposure to oxygen or corticosteroids. Such patients are likely to be severely immunocompromised under the combined influence of underlying illness, drugs used to treat their condition, corticosteroid and radiation therapy, and an opportunistic lung infection is a strong consideration [4]. Diagnosing drug-induced disease is even more complex in recipients of hematopoietic stem cell transplants, who in addition to the above complications, may develop several distinctive post-transplant manifestations, including engraftment syndrome, pulmonary edema, bronchiolitis obliterans organizing pneumonia (BOOP), diffuse alveolar hemorrhage (DAH) and late-onset noninfectious pulmonary complications including idiopathic pulmonary syndrome (IPS) [5, 6]. In rare instances, pulmonary complications develop in hematopoietic stem cell donors in the form of pulmonary infiltrates during colony-stimulating ­factor-(CSF)-induced stem cell mobilization [7]. The older literature is replete with cases of pulmonary toxicity induced by drugs such as busulfan, BCNU or other nitrosoureas, bleomycin, chlorambucil, cyclophosphamide, hydroxyurea or melphalan when patients with varied hematologic conditions were exposed to these drugs as a solo agent. Sometimes, the pattern of pulmonary involvement from these drugs is distinctive and can still be detected even though the drug is part of a multiagent chemotherapy or conditioning regimen. Establishing which drug in the regimen causes the lung injury is useful, for it may enable withholding the specific drug instead of all drugs in the regimen. Diagnosing drug-induced lung disease is not of pure academic interest. An important practical consequence is selective drug withdrawal while other nonpneumotoxic drugs are continued to the benefit of the patient. Although rechallenge was once considered hazardous and still is with many drugs, rechallenge and steroidsupported rechallenge can be attempted with vital drugs such as imatinib or dasatinib. Here we review the pulmonary complications induced by drugs, blood transfusion and radiation therapy.

31  Pleuropulmonary Changes Induced by Drugs in Patients with Hematologic Diseases

­ rug-induced opportunistic infections, respiratory manD ifestations in recipients of bone marrow and stem cell transplant and iatrogenic complications of chest tubes and central venous access are covered elsewhere [8, 9].

31.2 Diagnostic Criteria for Drug-Induced Respiratory Disease Criteria for diagnosis include the following [10]: 1. Correct identification of the drug [11] Dose and duration of treatment with each drug taken in isolation or in a chemotherapy regimen should be reviewed. Causality is more difficult to assess when several pneumotoxic drugs were received concomitantly or in sequence. The likelihood and delay time for drug-induced disease to present vary with drug, dosage, whether the drug was coadministered with other pneumotoxic drugs and the patient. Patients of Asian descent may be at increased risk for certain drug-induced pulmonary complications. It is also necessary to compute exposure to G/GM-CSF, blood and blood components (e.g., fresh frozen plasma, whole blood-derived platelets), anesthetic agents, oxygen, parenteral nutrition and nonhematologic drugs, for all of these may effectuate lung injury [11]. 2. Temporal eligibility Respiratory signs and symptoms should follow (not predate) the onset of treatment with the suspected drug. Time to onset of the respiratory reaction varies with drug, host, schedule of administration and pattern of involvement. The shorter the latency period is, the easier the suggestion of the drug etiology. Longer delay times increase the likelihood that the drug etiology goes unrecognized. Drug-induced- bronchospasm, anaphylaxis, pulmonary edema (e.g., gemcitabine- or acaytine-induced), acute lung injury (e.g., transfusionrelated acute lung injury or TRALI), acute respiratory distress syndrome (ARDS) and alveolar hemorrhage tend to develop shortly after exposure to the causal agent, with a time to onset of minutes to hours or at most a few days. Instead, it may take weeks, months or years for drug- (viz. methotrexate, azathioprine or thalidomide) induced cellular interstitial pneumonia to develop. Drug- and radiation-induced pulmonary fibrosis develops after months or years into treatment or after termination of treatment. For instance, patients

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who received busulfan, cyclophosphamide, nitrosoureas or radiation therapy in the past may be diagnosed with iatrogenic pulmonary fibrosis or the idiopathic pulmonary syndrome many years later [12, 13]. 3. Drug singularity Assessment of causality is problematic if patients were exposed to several pneumotoxic drugs. This creates confusion about which drug is responsible for the lung reaction, and it may at times be impossible to sort this out. In patients treated with several chemotherapy agents, drug toxicity may develop at dosages of each drug that are lower than the threshold above which drug toxicity develops when the drug is taken in isolation. Weighing the responsibility of each drug taken separately is critical regarding future management of the underlying hematologic disease. Identification of the causal drug may enable selective cessation of the culprit drug. A review on nonhematology drugs is indicated, as many drugs can injure the lung [11] 4. Whether the pulmonary reaction is appropriate for the particular drug The pattern of involvement from some drugs can be suggestive, owing to the close temporal relationship of exposure versus onset of respiratory symptoms (e.g., the swift development of pulmonary infiltrates following treatments with anti-thymocyte globulin, gemcitabine, ATRA, cytarabine or blood transfusion (TRALI) [14]. For other drugs it is because the clinical, imaging, BAL and/or pathologic pattern of involvement is distinctive [e.g., bleomycin and bibasilar shadowing or multiple lung nodules, cyclophosphamide and severe pleuropulmonary involvement, imatinib or dasatinib and pleural effusion, methotrexate and an acute hypersensitivity pneumonitis with a granulomatous pattern of involvement, rituximab and ARDS; retinoic acid (ATRA) and diffuse alveolar hemorrhage (DAH), of BCNU/CCNU or busulfan with otherwise unexplained pulmonary fibrosis]. It is difficult to predict the pathologic background of drug-induced reactions using HRCT data alone [15], and in one study of 20 patients [16], imaging and pathology were concordant in only nine cases (45%). A confirmatory lung biopsy (open or transbronchial) can be necessary in selected cases mainly to discard etiologies other than drugs rather than to prove the drug etiology. Any attempt at deducing pathology from imaging as done in some studies [17] should be viewed with caution.

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5. Exclusion of other causes There are many diagnostic contenders to consider when pulmonary infiltrates develop in patients with hematologic disease treated with drugs. These include the pulmonary manifestations of the native benign or malignant hematologic condition (for instance, pulmonary involvement from malignant lymphoma [15] or acute leukemia [18], extramedullary hematopoiesis [19], multiple myeloma [20–22], interstitial lung disease including pulmonary alveolar proteinosis that may occur in association with untreated hematologic diseases [23]), capillary leak, tumor lysis syndrome, cardiac pulmonary edema, an opportunistic viral, bacterial, fungal or protozoan infections including Pneumocystis jiroveci pneumonia, a common encounter in hematology patients [24–28], and a graft-versushost reaction [29]. All of these can produce similar patterns of involvement on imaging. The BAL and TBLB with appropriate sample staining, culture and molecular techniques should be routinely performed to help exclude an infection [2]. Heart ultrasonography and diuresis may also aid in the recognition of druginduced vs. cardiogenic pulmonary edema. 6. Remission of signs and symptoms with removal of the drug Signs and symptoms typically clear after drug removal. However, fulminate iatrogenic reactions to drugs (e.g., drug-induced pulmonary edema, TRALI, methotrexate pneumonitis, bleomycin lung) may progress despite removal. Similarly, pulmonary fibrosis induced by drugs or that develops as a late consequence of conditioning regimens often is an irreversible process that may not respond to drug discontinuance. Corticosteroid therapy is often given to patients with severe druginduced lung disease to accelerate recovery. However, this is at the expense of drug causality assessment. 7. Recurrence with rechallenge Rechallenge followed by recurrence is central to the diagnosis of any drug-induced disease [10], but seldom is performed intentionally because of risks [30]. Of note, drug-induced pleuropulmonary reactions to imatinib [31], dasatinib [32] or antithymocyte globulin [33] were shown not to relapse in all patients upon reexposure, enabling continued treatment of the underlying hematologic disease. Rechallenge is reserved for cases where the drug is vital, there is no alternative efficacious drug to treat the underlying condition, and it is given in small incremental doses of the drug and corticosteroid therapy.

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8. Tests may support the diagnosis of DILD BAL is instrumental in ruling out an infection and may show an increased percentage of lymphocytes, eosinophils or neutrophils depending on which drug caused the reaction (for a review, see [14]). Studies of peripheral or BAL lymphocyte activation or migration following in vitro challenge with the suspected drug have produced inconsistent results, and overall, evidence for the usefulness of this test is low, and there is a lack of consensus about the appropriateness of these tests inasmuch as in a recent series, there was no correlation of lymphocyte stimulation with the clinical result effect of rechallenge with the drug [34]. KL-6 has been found to be elevated in some patients with drug-induced fibrosis. However, this marker remained normal in cases of pulmonary toxicity from rituximab, methotrexate and radiation therapy. Similarly, time-related changes in plasma or BAL TGF-ß1 and IL1 in patients receiving chemotherapy and/or radiation therapy yielded inconsistent results, and there is no consensus regarding their measurements in routine. Areas of drug-, radiation- and talc-induced reactions can be tracer-avid on FDG-PET scans [35].

31.3 Patterns of Reactions to Drugs and Radiation 31.3.1 Interstitial-Infiltrative Lung Diseases (ILD) ILD is a group of conditions characterized by pulmonary infiltrates, restrictive physiology, impaired gas exchange, shifts in BAL cells percentages (lymphocytes, eosinophils or neutrophils) and pathologic evidence of parenchymal inflammation. Fever, a nonproductive cough and dyspnea are common presenting symptoms. Diagnosis of drug-induced ILD is supported by BAL, a negative workup for lung infection and reversal of the symptom following drug removal. Tissue sampling is not always required. Severity of ILD ranges from mild transient pulmonary infiltrates and the asymptomatic state to diffuse shadowing or dense consolidation with the gas exchange features of ALI or ARDS [36]. Histological findings are dominated by interstitial inflammation with or without tissue eosinophilia or a granulomatous pattern

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of involvement, organizing pneumonia, pulmonary edema, diffuse alveolar damage (DAD) or alveolar hemorrhage. The lung architecture is retained [37].

31.3.1.1 Cellular or Nonspecific Interstitial Pneumonia Drug-induced cellular interstitial pneumonia, also known as alveolitis or hypersensitivity pneumonitis, is a common pattern of pulmonary reaction to drugs [11]. Drugs causing cellular interstitial pneumonia in hematology include azacytidine, azathioprine, chlorambucil, 2-chlorodeoxyadenosine (cladribine), cyclophosphamide, cytarabine, dasatinib, floxuridine, fludarabine, GM-CSF, gemtuzumab, hydroxurea, imatinib, interferon alpha and beta, lenalidomide, methotrexate, procarbazine, rituximab, thalidomide, vinca alkaloids and chest radiation therapy [11]. Time to onset is a few days to several years into treatment and is unpredictable as serial pulmonary function is not capable of predicting development of this complication. Onset of the disease may be insidious over a few days or weeks, with moderate fever followed by the development of cough and breathlessness. Methotrexate lung is known to accelerate, causing rapidly progressive respiratory failure. Radiographic studies indicate bilateral, usually symmetrical interstitial or alveolar ground-glass opacities, mosaic attenuation or consolidation. The infiltrates may predominate in the lung bases and mid-lung zones, or they can be diffuse. Radiographic attenuation can be a discrete haze, ground-glass, inter- or intralobular septal thickening, a crazy-paving, mosaic appearance or dense bilateral consolidation with air bronchograms [38–42]. A miliary pattern, pleural effusions and mediastinal lymph node enlargement are occasional features of methotrexate lung [36, 43]. Imaging features may not enable the separation of ILD due to drugs from infectious pneumonia or from the manifestations of the underlying hematologic condition [26, 44, 45]. Pulmonary function indicates restrictive physiology and impaired gas exchange [36]. Physiology tends to correlate with the extent of involvement on imaging [46] except in azathioprine pneumonitis and bleomycin lung [47, 48]. Fiberoptic bronchoscopy and BAL are indicated to rule out an infection. The BAL usually shows a lymphocyte predominance [49]. The contribution of lymphocyte typing is unclear, because increases in both CD4+ or CD8+ subsets have been observed

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depending on time from onset of pneumonitis and whether the patient has received corticosteroid therapy [50]. A low ratio of CD4+ to CD8+ lymphocytes is suggestive for the drug etiology, but this is not a specific finding. Other BAL patterns include neutrophilia or a pattern of lymphocytosis and neutrophilia or eosinophilia. BAL samples should be processed with special stains, cultures and molecular techniques for the detection of bacteria, fungi and protozoa and viruses, including the recently recognized metapneumovirus and H1N1 [51]. A lung biopsy may be required in selected cases, since drug-induced lung disease may be a mimic of Pneumocystis pneumonia [52] and other opportunistic infections [53]. The TBLB approach can document interstitial pneumonia although sample size may be an issue. Histopathological features include interstitial inflammation, edema and a cellular interstitial infiltrate. Less common findings include granulomas during treatments with methotrexate [43], interferon [54] or lenalidomide [55], organizing pneumonia with rituximab or thalidomide, and interstitial fibrosis [43]. Alveolar edema or hemorrhage may be found as a manifestation of severe ILD [43, 56]. Management includes drug removal and supportive care. This may suffice in benign cases [57]. Corticosteroids are indicated in severe cases once an infection has been reasonably ruled out. Oral prednisolone or i.v. methylprednisolone daily for a few days is indicated depending on severity, followed by a tapering dosage of oral corticosteroid therapy. Mega-doses of methylprednisolone of 1 g/day are given to patients in some countries, with no documented benefit compared to a standard dose regimen. Fatalities have been reported in patients with severe disease, particularly if corticosteroids were not given in time and in patients rechallenged with the drug [30]. Lung fibrosis following recognition and treatment of this problem is seldom seen. Although rechallenge with the drug may not be followed with relapse [32, 58], this should be discussed on an individual basis. Patients and caregivers should be instructed to avoid unjustified reexposure to the drug or to a congener.

31.3.1.2  Eosinophilic Pneumonia The association of pulmonary infiltrates with blood and/or tissue eosinophilia defines eosinophilic pneumonia. This is an uncommon pattern of lung response

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to drugs used in hematology, contrasting with nonsteroidal antiinflammatory drugs and minocycline. Causal hematology drugs include bleomycin, chlorambucil, cladribine, cotrimoxazole, fludarabine, GM-CSF, interferon, inhaled or parenteral pentamidine, procarbazine and radiocontrast media. More common causal agents include nonsteroidal antiinflammatory drugs or minocycline [11]. Adverse reactions to methotrexate or blood transfusion can be accompanied by mild peripheral eosinophilia, but the BAL and pathologic features are not those of eosinophilic pneumonia. Onset of the condition is unpredictable. Acute eosinophilic pneumonia may produce acute respiratory failure. Unusual PIE cases present with rash and internal involvement, and this has been aptly coined DRESS for drug-rash and eosinophilia with systemic symptoms. A few DRESS cases were described with the use of azathioprine, bortezomib, hydroxyurea and imatinib [59]. On imaging, PIE is in the form of the photographic negative of pulmonary edema, or it is disseminated with faint shadowing, discreet ground-glass, Kerley “B” lines, or dense and diffuse infiltrates. An increase in blood, BAL and/ or lung tissue eosinophils is diagnostic. The lung biopsy rarely is required and shows an interstitial infiltrate of eosinophils admixed with mononuclear cells. Drug discontinuance is indicated. Corticosteroids are reserved for severe cases. Outcome is good.

31.3.1.3 Interstitial Lung Disease with a Granulomatous Component Granulomatosis has been reported in a few patients after treatment of non-Hodgkin’s disease in the form of reticulo-nodular infiltrates and/or medisatinal lymphadenopathy [60, 61]. Most cases of drug-induced granulomatosis with or without extrathoracic organ involvement and hypercalcemia are related to treatments with interferon alpha or beta. Methotrexate and lenalidomide can also produce a granulomatous pulmonary reaction (see below under interferon and methotrexate).

31.3.1.4 Organizing Pneumonia Organizing pneumonia (OP/BOOP) is a distinctive pattern of lung response to a few drugs and to hematopoietic stem cell transplantation as well, which

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is best defined by the pathologic finding of alveolar and ductal buds of connective tissue or fibrosis. Strictly speaking, organizing pneumonia is best diagnosed when a large sample of lung tissue is available for review to make sure BOOP is not an incidental finding among other more distinctive pathologic features. Claimed cases of BOOP without pathologic evidence are equivocal. This is not trivial, for pulmonary aspergillosis and BOOP can be indistinguishable on imaging [53]. Causal drugs used to treat hematologic conditions include bleomycin, busulfan (mostly the acute busulfan lung), cyclophosphamide, interferon, lenalidomide, rituximab, thalidomide and chemotherapy [11, 62]. At any rate, the diagnosis of drug-induced BOOP is against the background of BOOP, which can occur as a late noninfectious pulmonary complication in hematopoietic stem cell transplant recipients [5]. BOOP can manifest with chest pain, dyspnea and areas of consolidation or without respiratory failure [63], or it is discovered incidentally on imaging [64]. Nodular organizing pneumonia is a distinctive pattern of bleomycin pulmonary toxicity and is in the form of roundshaped areas of consolidation that may localize in lung bases and simulate metastatic lung disease [65]. A lung biopsy may be required to exclude this possibility [66], although clinical reasoning and observation coupled to 18F-dideoxyglucose PET scanning may suffice [67]. There is no BAL pattern that is characteristic of this condition. The percentage of lymphocytes and/or of neutrophils or eosinophils can be increased. If a lung biopsy is contemplated, the video-assisted approach is preferred as a larger sample lends greater support to the diagnosis. Histology reveals interstitial inflammation, superimposed on the dominant background of alveolar and ductal fibrosis [68]. Some patients present with overlapping features of organizing and eosinophilic pneumonia [66]. Drug discontinuation with corticosteroid therapy in severe cases is followed by improvement.

31.3.1.5 Diffuse Alveolar Damage and the Chemotherapy Lung The treatment of hematologic malignancies with chemotherapy agents, particularly alkylating agents but not exclusively so, may induce a pattern of lung derangements termed the “chemotherapy lung,” a wideranging term [14, 69]. Patients treated for leukemia,

31  Pleuropulmonary Changes Induced by Drugs in Patients with Hematologic Diseases

particularly patients with high blast counts during remission induction [70], Hodgkin’s disease or nonHodgkin’s lymphoma and recipients of bone marrow or stem cell transplant are at risk. The entity refers to nonhemodynamic, noninfectious and nonneoplastic pulmonary complications, which develop in a variable proportion of patients (<1–60% in some phase I or II studies) following administration of single-agent (e.g., BCNU or other nitrosoureas, bleomycin, bortezomib, busulfan, chlorambucil, cyclophosphamide, docetaxel, gemcitabine, melphalan, methotrexate, procarbazine, vinblastine) or multi-agent chemotherapy, particularly when drugs were used at elevated dosages or there is an association of several lung-toxic drugs with or without radiation therapy in the treatment schedule [71–73]. Substitution of one agent in a chemotherapy regimen can markedly alter the safety profile. For instance, in patients with de  novo-treated Hodgkin’s disease, the substitution of gemcitabine with dacarbazine in the ABVD regimen [doxorubicin, bleomycin, vinblastin, gemcitabine instead of dacarbazine (ABVG)] resulted in an unacceptable 42% incidence rate of pulmonary toxicity [74]. Likewise, in a phase I/II dose-escalation study in 27 patients with advanced-stage Hodgkin’s disease, the substitution of gemcitabine for etoposide in the escalated BEACOPP regimen (bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone and gemcitabine instead of etoposide) resulted in pulmonary toxicity in 29.6% of the patients [75]. Crucially, the disease needs be separated from an infection, mainly pneumonia due to Pneumocystis jiroveci or viral agents [76], acute heart failure and an acute transfusion reaction [77, 78]. If investigation of the sputum, BAL, blood and other fluids is unrevealing, especially on two consecutive evaluations for an infection, the diagnosis of chemotherapy lung is entertained further. It is challenging to assess the specific responsibility of each drug in the regimen to the syndrome if patients have received several pneumotoxic agents concomitantly or in sequence. Assessing causality is important though, for identification of the causal drug may allow selective drug discontinuation rather than withdrawal of all drugs in the chemotherapy regimen. It may be possible to discern methotrexate or bleomycin pulmonary toxicity when it occurs in patients receiving a multi-agent chemotherapy regimen. For instance, non-Hodgkin’s lymphoma patients who received m-BACOD or m-ACOD regimens developed a picture similar to methotrexate lung, whereas

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no pulmonary infiltrates were observed in patients receiving the CHOP regimen, which does not include methotrexate [79]. Similarly, the different incidence of pulmonary events in two arms of a therapeutic regimen that differed by only one drug (for instance with or without bleomycin, BCNU, CSF, gemcitabine, or radiation therapy) or by the dosage of one particular drug (e.g., low vs. high BCNU) enabled deducing which drug was exactly causing the reaction [80]. The likelihood of developing chemotherapy lung is increased when radiation therapy to the chest, TBI, oxygen, and possibly CSFs are given concomitantly. The term ‘chemotherapy lung’ is not ideal, because non-chemotherapy agents such as ATRA, IL-2 and imatinib, oxygen, transfusion of blood or proteins including IVIG, infusion of stem cells, radiation therapy and nonchemo agents can also cause the syndrome [11]. In addition to the intrinsic risk attendant to specific drugs, with busulfan carrying an extra risk compared to other chemotherapeutic agents [81], other factors include advanced age, current smoking, drug dosage and intensity of the conditioning regimen [myeloablative vs. nonmyeloablative, multi-agent combination chemotherapy, abrupt corticosteroid withdrawal, the type of stem cell transplantation (allogeneic vs. autologous, T-cell depleted) and a background of graft-vs.host reaction in transplant recipients]. Time to onset of the chemotherapy lung is variable from shortly after the first administration of low doses of the drug [70, 82] to months into treatment or after termination of treatment. Usual doses of oral corticosteroids may not prevent the condition from developing. Depending on patient and time of diagnosis, the chemotherapy lung may have overlapping features with, and be difficult to distinguish clinically and on imaging from acute pulmonary edema, diffuse alveolar hemorrhage, accelerated pulmonary fibrosis or dense interstitial pneumonias. The main histopathological feature of chemotherapy lung is diffuse alveolar damage (DAD) with, characteristically, hyaline membranes and fibrin deposits lining the alveolar border, dysplasia of type II cells, free alveolar fibrin, cells and debris in alveolar spaces, and various stages of interstitial edema and alveolar inflammation and organization [83–85]. Reactive type II pneumocytes are sometimes present in BAL mounts [86]. The term idiopathic pneumonia syndrome (IPS) or delayed pulmonary toxicity syndrome (PTS) is used in recipients of stem cell transplant [5] to denote late lung changes that may result

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from previously inflicted insult collectively induced by chemotherapeutic agents, conditioning regimens and total body irradiation [87, 88]. The clinical imaging expression of chemo- or chemo-radiotherapy lung is wide ranging [38–40, 89]. At one end of the spectrum, patients present with isolated dyspnea and a progressive decrease in the diffusing capacity as the only manifestation of toxicity [90]. Others present with bilateral interstitial and/or alveolar shadowing, which abates after discontinuation of the drugs and/or corticosteroid therapy [91]. Yet other patients with severe presentation progress to respiratory failure and respiratory death despite drug discontinuation [92]. The HRCT discloses scattered ground-glass haze, inter- and/or intralobular septal thickening or areas of condensation [40]. If patients are able to withstand the test, pulmonary function is restrictive, and hypoxemia is present. The diffusing capacity is decreased, and typically the decrease predates the onset of symptoms or the development of radiographic abnormalities. The changes are progressive or can be reactivated with further treatment with the causal drug, notably bleomycin or rituximab, and careful follow-up is needed before any further administration of the drug is contemplated [73, 90]. The BAL indicates an increase in neutrophils, or neutrophils and activated lymphocytes [93]. A lung biopsy is reserved for patients with an atypical presentation or those who do not improve on empiric antibiotic and steroid treatment [94]. Judicious use of lung biopsy may help to diagnose an infection and tailor treatment accordingly [2, 85]. However, the critical condition of these patients often precludes this option, as the procedure is associated with increased mortality when it is done in patients with significant respiratory impairment. In the setting of chemotherapy, the respective benefit of a minimally invasive approach with drug removal, empiric treatment with antibiotics and corticosteroids [95] as opposed to the more invasive approach remains unclear [96]. A fraction of patients respond favorably to drug discontinuation and corticosteroid drugs, especially if the condition is recognized early. For instance, in a series of 65 patients with hematologic malignancies who received a carmustine-based conditioning regimen prior to bone marrow transplantation, 17 (26%) developed pulmonary infiltrates thought to be drug-induced. Of these, 15 responded to corticosteroids [97]. One patient died of pneumonitis [97]. Corticosteroids should be tapered

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carefully to avoid catastrophic respiratory failure [98, 99]. Despite occasional success with immunosuppressive drugs [100], the response to treatment and the prognosis of this condition when it is advanced, when corticosteroids fail or when ventilatory support is required are disappointing. Chemotherapy-induced lung toxicity may also negatively impact on the management of the underlying hematologic disease, as a change in therapy may be required toward less efficacious or more toxic drugs. In patients who recover from chemotherapy lung, mild reduction of vital capacity and/or the diffusing capacity may persist in the long term [101], and the likelihood of permanent physiologic impairment is greater in smokers [102]. Patients who receive alkylating agents for Hodgkin’s disease or non-Hodgkin’s lymphoma should be discouraged from smoking, as persistent smoking greatly increases the likelihood of developing lung cancer later in life [103, 104]. The high incidence, severity and unpredictability of pulmonary complications from chemotherapy raise the question of whether early detection is meaningful using pulmonary function tests or imaging. Deterioration of indices of pulmonary function is common in patients exposed to chemotherapeutic agents [105, 106], including conditioning regimens for hematopoietic stem cell transplantation [107]. Changes cannot be predicted on an individual basis and occur more in patients who receive TBI in addition to drugs. Corticosteroids may mitigate or reverse these changes [107]. In the majority of patients, though, these subclinical changes do not predict the development of overt disease. In contrast, exposure to methotrexate does not alter lung functions [108]. Some investigators believe it is prudent to discontinue chemotherapy once the diffusing capacity has decreased to <50% of pretherapy values, while others do not rely on this measurement since it is their belief that the diffusing capacity does not equate to and may not predict toxicity, and there is the risk of unnecessarily withdrawing an effective chemotherapy [109]. An abrupt fall in the monthly measurement of the diffusing capacity may indicate impending toxicity. When radiation therapy is planned after administration of chemotherapeutic agents, it is advisable to wait for any chemotherapy-induced decrease in the diffusing capacity to stabilize or show a trend toward improvement, before the patient undergoes radiation therapy [90]. Although changes on imaging are common in patients receiving bleomycin or rituximab, it is impractical to

31  Pleuropulmonary Changes Induced by Drugs in Patients with Hematologic Diseases

rely on imaging to detect changes consistent with pulmonary toxicity of chemotherapeutic agents. Patients on chemotherapy may develop new opacities on CT although they never develop symptomatic disease [110]. There is no current agreement as to how patients on chemotherapy should be followed to reliably and cost-effectively detect meaningful therapyinduced pulmonary complications. However, many treating physicians have a chest radiograph, PFT and diffusing capacity measured serially during treatment, particularly if patients are being treated with bleomycin.

31.3.1.6 Cell Lysis Pneumopathy A subset of patients with acute leukemia and high blast counts may develop acute pulmonary complications during induction of remission in the form of diffuse pulmonary infiltrates and an ARDS picture with or without alveolar hemorrhage [111, 112]. This was coined cell lysis pneumonopathy [111] because the pathology indicates blasts in pulmonary capillaries and cell remnants or debris on a background of diffuse alveolar damage. [113]. In a recent study, pulmonary failure developed acutely (within 2 weeks of the initiation of chemotherapy) in 8% of 1,541 patients during remission induction. Male sex, acute promyelocytic leukemia, poor performance status, lung infiltrates at diagnosis and increased creatinine were risk factors for the development of this syndrome. Seventy-three percent of the patient died [70].

31.3.1.7 Drug-Induced and Iatrogenic Pulmonary Fibrosis The condition mostly develops in hematology patients treated with BCNU, bleomycin, busulfan, chlorambucil, cyclophosphamide, melphalan and/or radiation therapy/TBI. Less often, drug-induced fibrosis complicates treatments with gemcitabine, mercaptopurine, methotrexate and rituximab [11]. Drug-induced fibrosis may develop during treatment with drugs or it is diagnosed after termination of treatment. Imaging prior to onset of treatment with the drug helps confirm the time course of lung changes with respect to exposure to the drug or drugs, and enables separation from fibrosis of other causes. Early disease is in the form of

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linear or streaky opacities and loss of volume. Honeycombing is a late and inconsistent finding. For those patients who are still on the causal drug, drug removal may not be followed by improvement, and the response to steroids is often not gratifying. On histology, there is interstitial fibrosis, and the lung structure may not be retained. A reactive epithelium is suggestive of but not specific to exposure to alkylating agents and/or radiation therapy. In children or adults who have received cyclophosphamide for the treatment of hematologic malignancy, pleural and subpleural fibrosis can develop in addition to the more classic changes of pulmonary fibrosis [114]. This results in encasing of the lung, anteroposterior narrowing of the chest and severe restrictive physiology causing respiratory failure. It is unfortunate when the syndrome develops in a child, while the basic disease is cured. A few patients who received chlorambucil or methotrexate develop accelerated pulmonary fibrosis in the form of acute interstitial pneumonia [115, 116]. The outcome of pulmonary fibrosis is poor, despite drug withdrawal and institution of high-dose corticosteroids. Lung transplantation has been an option in a few patients.

31.3.1.8  Drug-Induced Pulmonary Edema Noncardiac pulmonary edema (NCPE) shows a classic pattern of response to several chemotherapeutic agents used to treat hematologic conditions. NCPE is due to the loss of integrity of the endothelial barrier and consequent fluid leakage. NCPE is characterized by the rapid or sudden onset of dyspnea, hypoxemia and ­alveolar infiltrates, with no evidence of left ventricular dysfunction or iatrogenic circulatory overload [although drugs used to treat malignancies may cause deterioration of cardiac function and cardiogenic pulmonary edema [117–121]. There is often close tem­ poral association of exposure to the drug, onset of dyspnea and the development of pulmonary infiltrates. Chemotherapeutic agents associated with NCPE include ATG, cytosine arabinoside, all-transretinoic acid (ATRA), amphotericin-B, arsenic trioxide (As2O3), bleomycin, blood and blood components, carmustine, CSF, cyclophosphamide, deferoxamine, docetaxel, doxorubicine, fludarabine, gemcitabine, interleu-kin-2, methotrexate, mitomycin, radiocontrast agents, ­rituximab, vinorelbine and vinblastine

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and several multiagent chemotherapy regimens [11, 122]. Most patients present with NCPE as an isolated finding, but in a few, weight gain, lower extremity or more diffuse edema and pleural and/or pericardial effusions suggest capillary leak [122, 123]. Pathology indicates bland pulmonary edema, with proteinaceous fluid filling most alveolar spaces and sometimes diffuse alveolar damage with little or no inflammation [37]. Severe cases can be fatal, but in most the infiltrates resolve with supportive care and corticosteroid therapy.

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Hematopoietic stem cell recipients may develop multiple pulmonary nodules in the context of fever a few months after infusion. Histological studies indicate sterile necrotic aggregates of leukocytes and a disrupted endothelium. The lesions have been coined pulmonary cytolytic thrombi [133]. Careful exclusion of malignancy and an infection is required in all cases, for infection due to Pneumocystis jiroveci, Aspergillus sp. and other fungi, HSP, Rhodo­ coccus, Mucor, Cryptococcus, Fusarium and tuberculosis can manifest with lung nodules.

31.3.1.9 Diffuse Alveolar Hemorrhage DAH is a unusual pattern of response to drugs in hematology patients [124]. This condition is on the background of DAH as a manifestation of the underlying disease with or without thrombocytopenia. Alemtuzumab, anticoagulants, ATRA, cytosine arabinoside and CSFs can produce this condition [11]. DAH can also occur with induction of remission in leukemia [125] and as a complication of hematopoietic stem cell transplantation [5, 29, 126, 127]. DAH is characterized by dyspnea, recent anemia, bilateral infiltrates and hypoxemia. The diagnosis is by BAL, which shows increased blood staining in sequential aliquots. DAH can be fatal [127].

31.3.2 Pulmonary Nodules Single or multiple nodules with the features of BOOP or circumscribed fibrosis on pathology may develop in children and in adults following treatments with aracytine, bleomycin, bleomycin and cyclophosphamide, and vinblastine [66, 67, 128–130]. Nodules can pose a difficult challenge in a patient with a history of malignancy, particularly when they assume a round shape. A critical review of other etiologies is necessary [131]. Close follow-up including imaging and 18F-dideoxyglucose PET scan is indicated. A lung biopsy may be required to confidently exclude malignancy. A patient with chronic lymphatic leukemia developed multiple shaggy lung nodules during treatment with fludarabine [132]. The nodules corresponded to sterile aggregates of mononuclear cells on pathology. They disappeared after drug withdrawal and corticosteroid therapy.

31.3.3 Acute Chest Pain White et  al. reported on 12 episodes of severe chest pain during infusions of bleomycin, suggesting the diagnosis of acute cardiac or pulmonary events [134]. Incidence of the syndrome was 2.8% of the patients being treated with the drug. Electrocardiographic changes suggestive of pericarditis were found in two cases and radiographic evidence of a small pleural effusion in one. The syndrome was self-limited or relieved with analgesics, and improvement was seen when the infusions were stopped. Further courses of bleomycin did not lead to recurrent episodes. There were no long-term sequelae. Substernal pain or pressure also was described during treatments with highdose etoposide [135, 136] and methotrexate [137]. The lupus syndrome induced by drugs (for instance interferon) may manifest with acute chest pain [138]. Infusions of 5-fluorouracil or etoposide can produce acute coronary spasm and consequent chest pain [136]. Chest pain is a recognized adverse event in stem cell donors during mobilization [139].

31.3.4 Bronchospasm Wheezing and bronchospasm are common symptoms in patients receiving antineoplastic drugs including monoclonal antibody therapy such as alemtuzumab or rituximab [140, 141]. Wheezing may be part of the “infusion reaction,” a constellation of symptoms including dyspnea, cough, facial flushing, skin rash or urticaria, pruritus, chest tightness and malaise. There

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is relapse upon rechallenge, except if pretreatment is given or the dose is reduced. Bronchospasm has been reported with the use of amphotericin B, l-asparaginase, amphotericin B, campath-1H, etoposide, GM-CSF, methotrexate, procarbazine, vinca alkaloids and corticosteroid drugs [11]. The excipients and solvents dimethylsulfoxide [142] and cremophor [143] have also been implicated. There is a close temporal relation of drug administration and wheezing, and in most patients symptoms are mild to moderate. Patients with bronchospasm could be successfully rechallenged using slower doses or infusion rate, or following premedication with antihistamines and corticosteroids. Some patients develop anaphylaxis, a life-threatening reaction with upper airway obstruction, severe bronchospasm, abdominal cramps and shock [144]. Drugs including antibiotics, anesthetic agents, oxaliplatin and blood can cause this condition [145, 146].

31.3.5 Pleural Involvement Pleural effusion can be present on imaging in patients with pulmonary reactions to methotrexate, procarbazine or ATRA, especially if the reaction is severe [11, 147]. Bleomycin, cyclophosphamide, IL-2, IVIG, methotrexate, ATRA and radiation therapy can produce lone exudative pleural effusions [11, 148]. Pleural thickening and retraction is a form of late cyclophosphamide toxicity [114, 149]. Pneumothorax can complicate fibrosis induced by BCNU, cyclophosphamide or bleomycin [150]. Radiation-induced pleural changes are mentioned below.

31.3.6 Late Changes Mild drug-induced reduction of vital capacity and/or diffusing capacity may persist for a few months in patients treated for hematologic malignancies. The likelihood of permanent physiological impairment is greater in smokers [102]. Follow-up of patients is required, especially in those who received a stem cell transplant, to monitor progressive changes (although their incidence is lower than it used to be [151]) and to

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detect post-treatment lymphoproliferative disease and other malignancies.

31.3.7 Drug-Induced Lymphoma and Second Cancers As basic disease-related mortality has decreased with time in patients with Hodgkin’s disease and non-­ Hodgkin’s lymphoma once remission is obtained, therapy-related mortality increases with time and is becoming the most prevalent cause of late deaths [152]. Although a downward trend in mortality has been noted in more recent years (1980–1995) compared to the prior treatment era (1962–1980), second cancers and cardiovascular complications still account for 20% and 14% of late deaths, respectively [152]. The risk of second or higher-order lung cancer in Hodgkin’s disease and non-Hodgkin’s lymphoma is increased [153], and it correlates with the dose of radiation delivered to the lung, amount of chemotherapeutic agents received and whether the patient is a smoker. In one study, the relative risk of lung cancer in patients who received ³9.6 Gy was 9.6 compared to <1 Gy. Patients who had smoked >10 pack-years after the diagnosis of Hodgkin’s disease had a further sixfold increase in risk, compared with patients who smoked <1 packyear. A positive interaction on a multiplicative scale was observed between the carcinogenic effects of smoking and radiation [103]. Studies have found a positive interaction between treatment with MOPP (mechlorethamine, vincristine, procarbazine and prednisone), the number of cycles and the risk of lung cancer [154]. Radiation therapy added to the risk [155]. In another study, treatment with MOPP was associated with a greater risk of lung cancer, compared to chlorambucil, vinblastine, procarbazine and prednisone [156]. Since tobacco use appears to synergize the risks from treatments and increase lung cancer risk more than 15to 20-fold, physicians treating these patients need to be wary of the risk and should make a special effort to dissuade patients with Hodgkin’s disease from smoking after receiving chemotherapy and radiotherapy. Smoking cessation is a vital part of long-term management of such patients. Incidence of pleural mesothelioma increases post-­ radiation therapy in malignant lymphoma survivors [157]

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31.4 Drugs Causing Pleuropulmonary Toxicity in Hematology 31.4.1 Amphotericin B Not uncommonly, infusions of amphotericin B produce wheezing and bronchospasm [11, 158]. Rarely, amphotericin evokes an anaphylactic reaction with or without upper airway obstruction [159]. Not all manifestations will return upon rechallenge, and there are guidelines to reexpose patients to the drug [160]. Wright et al. described 14 patients who developed pulmonary infiltrates and acute respiratory failure shortly after infusion of amphotericin B and granulocytes [161]. Lung biopsy and autopsy studies disclosed DAH and pulmonary edema. Other studies failed to confirm an association. The possibility of a TRALI syndrome induced by coadministered granulocytes is a  possibility. No further case has appeared in the literature. Infusion of liposomal amphotericin B or amphotericin in 20% intralipid can produce dyspnea, chest tightness, pulmonary infiltrates and pulmonary edema [162]. Histopathological studies in a fatal case evidenced fat embolism with lipid material in pulmonary capillaries [163].

31.4.2 Anti-thymocyte Globulin Transient pulmonary infiltrates thought to represent mild pulmonary edema or, less often, an ARDS picture have been described following anti-thymocyte globulin (ATG) infusion [164]. Rechallenge was followed by recurrence of pulmonary infiltrates [164]. In one recent report, steroid-supported rechallenge was not followed by relapse [33].

31.4.3 All-trans-Retinoic Acid (ATRA) and Arsenic Trioxide As2O3 All-trans-retinoic acid or ATRA, the active metabolite of vitamin A, and arsenic trioxide (As2O3) have emerged as important agents to induce remission in

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newly diagnosed or relapsed acute promyelocytic leukemia [165], where these agents accelerate the differentiation and maturation of normal promyelocytic cells, which quenched the life-threatening hemorrhagic complications of the disease at its onset. The administration of ATRA during induction of remission is often followed in a few days by a sharp increase in the number of circulating myeloid cells and neutrophils. This is temporally associated in some patients with the development of fever, weight gain, pleuritic chest pain, pleural or pericardial effusion, lower extremity edema, dyspnea, pulmonary infiltrates, pulmonary edema, alveolar hemorrhage, or an ARDS picture [166–169]. This aggregate of symptoms developed an average of 8 days after initiation of treatment and is grouped under the eponym “retinoic acid- or ATRA syndrome” [166]. Similar manifestations are observed in patients who receive As2O3 in up to 31% in one study [170], causing respiratory death [171]. The condition is also referred to as ATRA or retinoic acid syndrome. Onset of ATRA syndrome can be heralded by an increase in circulating neutrophils. Patients with neutrophil counts above 10,000/mL are considered at risk of developing the syndrome, while the condition is considered unusual in leukopenic patients [166]. ATRA syndrome is thought to result from the sequestration of activated neutrophils in pulmonary capillaries, leading to acute lung injury and vascular leakage. Radiographic studies indicate ill-defined infiltrates, ground-glass opacities, lung nodules that may progress to diffuse alveolar shadows, and pleural effusions [172]. Blasts and promyelocytes containing Auer rods were evidenced in the BAL in one case [173]. Postmortem studies indicate maturing and mature myeloid cells within the pulmonary interstitium [166]. Capillaritis and diffuse alveolar hemorrhage have been reported once [174]. Patients improve on drug removal and high-dose corticosteroids [166]. Prophylactic corticosteroids have decreased both the severity and incidence of ATRA syndrome down to about 8% [175]. Mortality from ATRA syndrome is about 8% or 1% of all patients treated with these agents. In most cases, ATRA therapy can be reinstituted once the syndrome has resolved [176], although at 75% of the initial dosage [177]. ATRA may also cause venous thromboembolism and infarction in several end organs, including the lung [178]. As2O3 may also cause adverse cardiac effects [179].

31  Pleuropulmonary Changes Induced by Drugs in Patients with Hematologic Diseases

31.4.4 Azacytidine The DNA hypomethylating agent azacitidine was approved for treatment of myelodysplastic syndrome. A few cases report the association of treatments with the drug and episodes of ILD, BOOP, or reversible ARDS [180–182]

31.4.5 Bis-Chlororethyl Nitrosourea Carmustine The bis-chlororethyl nitrosourea (BCNU, carmustine) drug derives from the vesicant chemical warfare mustard. BCNU is an alkylating agent introduced in 1963 in the treatment of malignant brain tumors because of its low molecular weight. Currently, BCNU is used for the treatment of high-risk breast carcinoma and as a conditioning regimen for bone marrow and stem cell transplantation along with busulfan or cyclophosphamide and total body irradiation (TBI). BCNU and TBI are thought to play a crucial role in the pathogenesis of chemotherapy lung and idiopathic pulmonary syndrome (see above). The lower incidence of idiopathic pulmonary complications with nonmyeloablative as opposed to myeloablative preconditioning regimens supports the causal role of the intensity of the conditioning regimen in its development. The pulmonary complications of BCNU when the drug was used as a solo agent have been described in children and in adults, and BCNU has caused pulmonary toxicity more often than the other nitrosoureas CCNU (lomustine), DCNU (chlorozotocin), methyl-CCNU, streptozotocine, fotemustine, and estramustine. Carmustine lung damage is dose-related, and the incidence is between 1% and 10%. BCNU pulmonary toxicity is one form of chemotherapy lung, and it resembles clinically, pathologically and on imaging the pneumonitis induced by bleomycin, busulfan, chlorambucil, cyclophosphamide, melphalan, and vinblastine. A total dose of 1,000–1,200 mg/m2 of BCNU is considered the threshold above which the incidence of pulmonary toxicity increases steeply when the drug is used as a single agent [183]. Incidence of BCNU toxicity increases about tenfold when cyclophospamide or irradiation is given concomitantly. Up to two thirds of patients

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treated with high-dose chemotherapy and BCNU develop clinical and physiological evidence of pulmonary toxicity [184]. An attempt to reduce pulmonary toxicity in a modified CBV regimen using CCNU instead of BCNU followed by autologous hematopoietic cell transplantation in 16 patients with relapsed or refractory Hodgkin’s disease or non-Hodgkin’s lymphoma was associated with a 63% incidence of interstitial pneumonitis, and 6 of 16 affected patients died of interstitial pneumonitis [185]. Early disease presents subacutely, a form of BCNU lung toxicity that is more amenable to corticosteroid therapy, thereby having an improved prognosis [107, 184]. Late BCNU toxicity is characterized by pulmonary fibrosis [186] and progressive respiratory failure [187]. The histopathological appearances of BCNU pneumonitis are similar to those from other alkylating agents with interstitial edema, diffuse alveolar damage, a reactive epithelium, and interstitial fibrosis [188–190]. Less common features include pleural fibrosis [189], vascular thrombosis, venoocclusive disease, or pulmonary alveolar proteinosis [187]. Longterm follow-up indicates that a fraction of patients with hematologic malignancies may die late from nitros­ ourea-related respiratory failure [191].

31.4.6 Bleomycin In the 1960s, bleomycin was one of the first drugs recognized as a cause of lung disease [192]. Bleomycin pulmonary toxicity (BPT) is common [193, 194] and there are recent reports in patients who received the drug with other antineoplastic agents for the treatment of malignant lymphoma [195, 196] or solid tumors [197, 198]. Many therapy-related pneumonitis cases that occur in patients receiving chemotherapy regimens containing bleomycin (e.g., ABVD, BACOD) are reported as BPT [196]. Onset of BPT is not as acute as that of methotrexate lung. BPT can be severe, but this form of toxicity may be less debilitating than busulfan, nitrosoura, or myleran lung. The characteristics of BPT may be discernible even though bleomycin is given along with other chemotherapeutic agents [193]. Even though early reports warned of the possibility of BPT after low cumulative dosages of the drug [199], for many

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years it was believed that bleomycin caused pulmonary toxicity only above 500 mg. In fact, although the incidence of BPT is dose-dependent [193], BPT can occur with as little as 20 or 34  mg bleomycin [200, 201]. Renal failure places patients at higher risk of developing BPT [79, 202], owing to decreased clearance of the drug. Slow as opposed to rapid i.v. infusion and intramuscular administration of bleomycin lessen the risk of BPT. Previous use of bleomycin should be considered in those patients requiring retreatment, as there is cumulative toxicity. In some but not all studies, advancing age was a risk factor for BPT. Concomitant or recent irradiation [203, 204], treatments with cyclophosphamide [205], and exposure to high concentrations of oxygen add to the risk and may trigger the onset of BPT [206]. Although not everyone will agree [207], it is prudent to request that anesthetists use the lowest possible fractional concentration of oxygen when patients with a history of exposure to bleomycin undergo any surgical procedure. In some but not all studies, a history of BPT negatively impacts overall survival of patients with malignant lymphoma [196, 208]. Incidence of BPT was once estimated to be 2–3% [209, 210], but recent figures are around 10–15% [196, 197, 202]. Recently, a 11.5% incidence of BPT was reported when bleomycin was administered with vincristine and cisplatin every 10 days [197]. Mortality is about 10%, and overall mortality was 2.3% in a study of 194 patients treated for germ cell tumors with this agent [202]. Mortality is higher in older patients, in those with renal failure [202], and in those with severe BPT, where mortality can be as high as 60% [209]. Clinically, BPT presents acutely or subacutely with dyspnea, and sometimes chest pain [134, 194, 210]. Some chest discomfort may be present at some point before BPT is suspected, representing early BPT that went unrecognized [210]. Crackles on auscultation may precede the radiographic changes of BPT. Imaging studies indicate the predominant involvement of the lung bases as opposed to the apices, costophrenic angles, and subpleural regions, and there is often generalized loss of lung volume [193, 211]. A retrospective review of chest films may show the gradual development of these changes, and it is easy to miss the actual onset of BPT. On HRCT in mild cases, a diffuse ill-defined ground-glass pattern or haze is ­present. Later, patients develop discrete subpleural ­crescent-like opacities, streaky opacities along the

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bronchovascular bundles, alveolar infiltrates, alveolar densities, consolidation, or the clinical-radiographic picture of ARDS [48, 194, 212, 213]. Changes on imaging correlate poorly with impairment of the diffusing capacity [48]. Some patients present with masses on imaging that may about the pleura [48, 214]. Pleural thickening or an effusion is an unusual finding. Several of the above mild HRCT findings are common (up to 80%) in asymptomatic patients during treatments with bleomycin [193]. However, they do not necessarily indicate toxicity, and drug discontinuance is not always required. In one study, such changes occurred in 15 out of 18 patients [215], none of which developed clinically recognizable disease. Thus, serial HRCT may not be a practical test to ensure early detection of BPT, which is best monitored using history, clinical examination, pulmonary function, and the chest radiograph. On pulmonary function tests a restrictive defect, hypoxemia, and a reduction in the diffusing capacity are present. A low diffusing capacity does not equate toxicity and may predate onset of overt toxicity by weeks. The BAL pattern is neutrophilic [216]. Pathologic features of BPT resemble those seen with the other alkylating agents such as busulfan, chlorambucil, cyclophosphamide, melphalan, and nitrosoureas. Tissue eosinophilia is uncommon and has been reported in patients with the diffuse [198, 217] and nodular (BOOP) [66] form of the disease. The development of parenchymal lung nodules in patients receiving bleomycin is almost unique to this compound, and it can be problematical [218], raising the possibility of parenchymal involvement from the underlying hematologic malignancy [66]. The area’s BPT can be tracer-avid on PET scan [35, 219]. Previous imaging, time course of disease markers, earlier PET scan, and response to chemotherapy will dictate whether watchful waiting is indicated or a lung biopsy is necessary so separate these entities. Nodular BPT corresponds to the histological pattern of BOOP with or without eosinophilia in the tissue. Nodular BPT may shrink or clear in a few weeks. Overall, the prognosis of BPT is less dismal than with the other alkylating agents. A sizable fraction of patients with BPT have reversible disease [194], even though there was evidence for fibrosis on pathology [220]. Corticosteroids are the mainstay of treatment, and, although no controlled study is available, there is clinical evidence for benefit of this form of treatment

31  Pleuropulmonary Changes Induced by Drugs in Patients with Hematologic Diseases

in mild or moderate BPT. Corticosteroid therapy can be without an effect in severe BPT [197]. It is considered that if patients survive the initial episode of BPT, they are likely to recover gradually [194]. Early or abrupt withdrawal of corticosteroids is discouraged, as this may lead to a severe relapse of BPT [209], and a slow taper is recommended. Some patients develop irreversible bleomycin-induced pulmonary fibrosis [221] with, ultimately, honeycomb lung and clubbing, and die from the condition [209]. The question of whether serial pulmonary function testing is useful in identifying patients who will develop BPT was assessed in 59 men with non-seminomatous testicular carcinoma (the findings probably apply to hematology patients as well) [110]. Patients received a three-course regimen consisting of vinblastine, bleomycin, and platinum. The average bleomycin dose was 555.5 units. Pulmonary physiology was serially evaluated prior to each treatment course. The ­diffusing capacity fell significant by 11.8% with bleomycin treatment. However, the diffusing capacity failed to predict which patients would develop clinical toxicity. The reduction in the total lung capacity had a better correlation with clinical toxicity [110]. Despite the inability of the diffusing capacity to detect patients who will develop clinical toxicity [110, 222], serial measurement of lung volumes and of diffusing capacity are still routinely performed in this population also for medical-legal reasons [223]. The diffusing capacity decreases in up to 75% of the patients treated with bleomycin, and in only a few will clinical toxicity develop [223]. Any asymptomatic impairment of the DLCO is likely to improve slowly upon termination of treatment. The lung of patients exposed to bleomycin in the remote past should be considered vulnerable, as suggested by occasional reports of unexpected ARDS after minor insults years after termination of treatment with this agent [224].

31.4.7 Blood and Blood Products: Transfusion-Related Acute Lung Injury TRALI is a potentially devastating complication defined by hypoxemic respiratory failure within 6 h of transfusion, once other causes are excluded. To some

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extent, TRALI is avoidable and can be prevented. By definition, acute lung injury is defined by a PaO2/FIO2 ratio <300, hence the term TRALI. However, some severe TRALI cases would deserve the eponym TR-ARDS, for the PaO2/FIO2 ratio in those cases is <200. TRALI is a noncardiogenic pulmonary edema that is temporally and mechanistically related to transfusion of blood and/or blood components. TRALI occurs within 6 h of transfusion. TRALI results from the sequestration of primed and activated neutrophils in the pulmonary circulation, thereby causing endothelial injury and consequent fluid leakage. TRALI is more common in ICU patients [225], and the condition adversely affects outcome. TRALI has a 10% attendant mortality and is the leading cause for transfusionrelated deaths [78, 225–231]. Although all blood components have been implicated in TRALI, those that contain a significant amount of plasma, namely fresh frozen plasma and whole blood-derived platelet concentrates, are exposed to a higher risk, compared to red blood cells or whole blood [230, 232]. Plasma-rich components carry a greater risk of containing a substantial quantity of antibody from a donor, which in the majority of cases is the cause of TRALI. Whole blood, immunoglobulins, stem cells, or, rarely, autologous blood have also been implicated [230, 232]. TRALI results from the transfusion of an antiHLA  I, -HLA AII, or human neutrophil alloantigen (HNA-3a-(5b)) antibody from one donor in the pool into patients whose leukocytes express the corresponding cognate antigens [230]. Such antibodies are found in 60–85% of cases. The case for a relationship is more compelling if concordance between the antigen specificity of the leukocyte antibodies in the donor plasma and the corresponding antigen on the cells of the affected recipient is demonstrated [233]. This is found in about 50% of cases. The antibody-antigen interaction causes complement-mediated activation and sequestration of neutrophils in the pulmonary circulation and intravascular cholesterol crystal formation [234], endothelial damage, vascular leakage, and consequent pulmonary edema [230, 234, 235]. Antibodies are more prevalent in women with a history of pregnancies, and the antibody titer increases with the number of pregnancies. Antibody prevalence is lowest in men and in nulliparous women. Although this antibody-antigen hypothesis is attractive, there are antibody negative TRALI cases, TRALI can occur in neutropenic patients, and there is one cause of TRALI

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following auto-transfusion. Understanding and recognizing TRALI are important. The responsible donor, generally a multiparous woman with high titers of antibody, should be identified. Laboratory investigations should be undertaken in donors to identify the antibody and in the recipient to determine whether his leukocytes bear the cognate antigen. Then the TRALI case can be classified into immune or nonimmune TRALI, the blood bank should be notified to quarantine other components from the same donation until the diagnosis is confirmed, and the implicated donor is identified. The implicated donor should be deferred from further blood donation or their blood diverted to prepare plasma-poor products, not whole blood, FFP, or platelets [232]. TRALI is poorly known [236], and it is underreported [237]. Incidence of TRALI is about 1 in 5,000 transfusions in the US (between 0.08% and 0.16% of all blood transfusions) and is less in Europe. Incidence is higher in ICU patients and in patients with a history of recent bypass surgery, recent infection, in patients with hematologic diseases, and in those who received CSF. This is consistent with a two-hit hypothesis for TRALI, whereby pulmonary endothelial cells are first activated, and PMN are primed and sequester in the pulmonary circulation. Then, transfusion of a biologic response modifier such as anti-granulocyte antibody or biologically active lipids activates adherent neutrophils resulting in endothelial damage vascular leakage and TRALI [238]. By definition, the symptoms of TRALI develop within 6  h of the transfusion in the form of abrupt respiratory failure with rigors, dyspnea, tachypnea, cyanosis, hypotension, leukopenia, mild eosinophilia “whiteout” of the lungs [239], and evidence for fluid leakage [240]. Severe cases are heralded by a proteinrich exudate at the mouth or in ventilator tubings [241]. Sudden intraoperative hypoxemia during blood transfusion or infusion of FFP should raise the suspicion of TRALI [242, 243]. Transient hypoxemia following blood transfusion in patients on the respirator may correspond to TRALI [238]. The main competing diagnoses include transfusion-associated circulatory overload or TACO (both conditions can coexist), transfusion-related sepsis, anaphylaxis, and hemolytic reactions [244]. Imaging studies and measurement of BNP levels may aid in separating TACO from TRALI [245], and an important distinction for diuretics is

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contraindicated in TRALI [230]. Once TRALI is s­ uspected, laboratory investigation should be undertaken on the remains of transfused products, in the recipient, and in donors whose blood or component were given within 6  h prior to the development of TRALI for the presence of antibodies [226]. Retrospective investigation can evidence an antibody in one donor in the pool in up 89% of cases [246], and a cognate antigen-antibody correlation was identified in 14 of 16 TRALI cases in one study [247]. Underrecognition and underreporting of TRALI may have detrimental consequences. A lookback investigation following a fatal case of TRALI indicated that administration of blood from the implicated donor had produced 15 previous adverse reactions in 14 patients, of which eight were severe [226]. Only two were reported to the regional blood collection facility, and the donor was not deferred from blood donation [226]. Other less common mechanisms for TRALI include antileukocyte antibody in the recipient that react with donor’s leukocytes [248] and shelf aging of blood products, leading to accumulation of lipidderived biologic response modifiers. Management of TRALI is supportive and includes judicious fluid management, oxygen, and mechanical ventilation in severe cases. Approximately three quarters of patients with TRALI need ventilatory support. The effect of corticosteroid drugs is controversial. Diuretics should be used with caution as TRALI often is associated with fluid leakage, and diuretic therapy may aggravate hemodynamic instability [249]. Diuretics are reserved for cases with documented fluid overload and/or left ventricular failure [244, 249]. Most TRALI cases will recover within 96 h. Prevention of TRALI relies on parsimonious use of blood transfusion, particularly of plasma rich blood components and in the ICU. Other measures include blood washing to remove biologically active substances, the use of solvent-detergent plasma, improved donor selection, male predominant or male only policy, which is associated with a reduction in the incidence of TRALI, and minimization of shelf life of blood products. Awareness, proper recognition, and reporting of TRALI are essential. Screening blood donors or testing donors with a history of pregnancy or transfusion is a logical and cost-effective TRALI prevention strategy. However, this may not meet with

31  Pleuropulmonary Changes Induced by Drugs in Patients with Hematologic Diseases

success, as not all blood components with antibodies will produce TRALI in the clinic.

31.4.8 Bortezomib Treatments with the proteasome inhibitor bortezomib have been associated with the development of pulmonary infiltrates [250–253]. The incidence is 3% in Japan and is less in the West. The highest recorded incidence was 31% [254]. Corticosteroid therapy may prevent the development of bortezomid-associated pulmonary infiltrates. The condition needs be separated from the pulmonary manifestations of multiple myeloma, which include plasma cell infiltrates and crystal-storing histiocytosis, and from an infection [20, 22].

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carcinoma who receive chemotherapy regimens including this drug, although the lung illness in these cases is not coined busulfan lung any longer [257].

31.4.10 Chlorambucil Chlorambucil is prescribed primarily for the treatment of chronic lymphatic leukemia and low-grade lymphomas. The clinical imaging presentation and pathologic features of chlorambucil pulmonary toxicity are not dissimilar to those described in other alkylating agentinduced pulmonary toxicity [263–265]. Notably, there are atypical changes in alveolar lining cells. A handful of cases of seemingly cellular interstitial lung disease have been reported, with recovery following drug discontinuance and corticosteroid therapy [265]. One recent case report of focal BOOP is thought to reflect chlorambucil pulmonary toxicity [266].

31.4.9 Busulfan (Myleran) Most cases of busulfan lung were described in the 1960s and 1970s [255], when the drug was used as a single-agent for the treatment of chronic myelogenous leukemia [256]. Nowadays, busulfan is mainly used in conditioning prior to hematopoietic stem cell transplantation, where busulfan pulmonary toxicity is enhanced by drug dosage as seen in recipients of autologous stem cell transplant [257] and by concomitant irradiation [257]. Time to onset of busulfan lung is from a few weeks to 10 years. Administration of other chemotherapy agents increases the risk of developing the condition. Busulfan lung is notable for hugely reactive alveolar cells in the lung and in other epithelia [258], pulmonary fibrosis [259], and, less commonly, a pattern of organizing pneumonia [260], or pulmonary alveolar proteinosis [261]. Long-term exposure to busulfan may produce a brownish discoloration of the skin simulating Addison’s disease [256]. Although the incidence of busulfan lung is relatively high, with figures up to 6%, the disease is difficult to predict as pulmonary function of unaffected patients may remain unchanged during treatment [262]. Although reports of pure busulfan lung have decreased in the past years, busulfan pulmonary toxicity continues to afflict patients with hematologic malignancies or breast

31.4.11 Colony-Stimulating Factors Colony-stimulating factors (G & GM-CSF) stimulate the production of neutrophils from committed hematopoietic progenitor cells. These agents are used to restore neutrophil counts in patients who are receiving myeloablative chemotherapy or have aplastic anemia, and to mobilize progenitor cells in stem cell donors. A few case reports described pulmonary infiltrates in patients receiving G-CSF monotherapy [7, 267, 268]. Most cases described pulmonary infiltrates or ARDS in patients who were being treated with chemotherapeutic agents (bleomycin, busulfan, methotrexate, or TBI) in conjunction with G- or GM-CSF [208, 269]. In a series of 36 patients with non-­ Hodgkin’s lymphoma receiving a BACOP regimen, 12 received recombinant G-CSF. Out of these 12, four developed respiratory complications (3 died), as opposed to 1 of 24 unexposed patients [270]. Other reports reported fatal respiratory distress in patients receiving CSF for hematologic malignancies [271] or nonneoplastic conditions [271]. Experimental evidence indicates that G-CSF leads to sequestration of activated neutrophils in lung [272] and enhances the damage from bleomycin [273].

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However, a randomized study in patients with germ cell tumors failed to demonstrate an increase in incidence of BPT in patients who were exposed G-CSF compared to bleomycin controls [274]. In several patients, but not in all, pulmonary infiltrates developed concomitant with CSF-induced peak in circulating neutrophils [275]. A few cases were described in patients who had persistently low neutrophil counts. Clinical severity ranged from transient subclinical hypoxemia [276] to diffuse pulmonary infiltrates or an ARDS picture [276]. Lymphocytosis was found in the BAL in one case [277]. CSF-associated infiltrates cleared in a few days or they persisted for weeks. Mortality is about 20%, and prognosis is improved on corticosteroid therapy [275]. Rechallenge may not lead to relapse of the pulmonary infiltrates [275]. CSF-induced mobilization in donors can also induce pulmonary complications. These range from a subclinical drop in PaO2 with a widened A-a oxygen gradient [278] to pulmonary infiltrates, ARDS, or capillary leak and pleuropericardial effusion [7, 268, 278, 279].

31.4.12 Corticosteroids Long-term corticosteroid therapy leads to mediastinal lipomatosis, a radiographic curiosity in most patients and a cause for cough or mediastinal hemorrhage in a few [280, 281]. Corticosteroids may induce respiratory muscle weakness, with consequent restrictive lung dysfunction [282]. Allergy and anaphylaxis are rare [283–285]. Corticosteroids exert a broad range of immunosuppressive activities [286], and patients on corticosteroids long-term run the risk of developing opportunistic pulmonary infections, including Pneumocystis jiroveci pneumonia [8].

31.4.13 Cyclophosphamide Like busulfan and nitrosoureas, cyclophosphamide is an alkylating agent used in the treatment of various forms of leukemias and lymphomas and as a conditioning agent prior to stem cell transplantation. Cyclophosphamide may produce early or late pleuropulmonary toxicity [114].

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Early cyclophosphamide pulmonary toxicity resembles that of other alkylating agents, is associated with BAL lymphocytosis [287], and is reversible upon removal of the drug, except in patients who develop early ARDS [288]. The prognosis of early cyclophosphamide pulmonary toxicity exceeds that for the nitrosoureas and busulfan, and if diagnosed early, this form of cyclophosphamide pulmonary toxicity is largely reversible upon removal of the drug and institution of corticosteroid therapy. It is important to rule out an infection [289], especially Pneumocystis jiroveci pneumonia, which is difficult to differentiate from, and can coexist with cyclophosphamide pneumonitis [290]. Late cyclophosphamide pulmonary toxicity mostly follows chronic oral exposure [114, 291], occurring with up to 13 years of treatment [292]. Chronic cyclophosphamide pneumonitis takes the form of progressive pulmonary fibrosis with respiratory failure, and sometimes digital clubbing is present [293]. The peculiar feature in a subset of patients with late cyclophosphamide toxicity is a pattern of pleuropulmonary fibroelastosis that involves the upper and lateral aspects of the pleura, which is thickened, in addition to more conventional changes of pulmonary fibrosis of the underlying lung [114, 149, 294, 295]. Progressive narrowing of the anteroposterior aspect of the thorax may develop in children, contributing the restrictive physiology, which is progressive with time [149, 296]. Pneumothorax may complicate this form of late cyclophosphamide pleuropulmonary toxicity, and it is difficult to treat as the underlying fibrotic lung reexpands poorly. Chronic cyclophosphamide pneumonitis is irreversible, even with drug withdrawal and institution of corticosteroid therapy [114].

31.4.14 Cytosine-Arabinoside (Ara-C) Treatments with high-dose Ara-C can be complicated by transient pulmonary infiltrates or pulmonary edema [297–299]. The condition develops in close temporal association with administration of the drug [299, 300]. In a series of 181 autopsies of patients with leukemia, unexplained massive proteinaceous pulmonary edema correlated with recent administration of Ara-C [297]. Pathology discloses bland alveolar flooding by proteinaceous material, suggesting acute fluid leakage [301]. Little or no inflammation is present. Less severe

31  Pleuropulmonary Changes Induced by Drugs in Patients with Hematologic Diseases

cases show diffuse alveolar damage [85]. Several case histories are consistent with a beneficial effect of corticosteroid therapy in aracytine-induced pulmonary edema. Recently, acute pulmonary edema and bilateral pleural effusion were diagnosed in a patient who received methotrexate 1,000 mg/m2 daily and cytarabine 3,000  mg/m2 twice a day on day 2 and 3 and G-CSF [302]. A patient who received 10 mg/m2 mitoxantrone daily for 6 days and 3 g/m2 IV ARA-C developed histologically documented BOOP. Chagnon et al. described transient centrilobular nodules in six patients with acute myelogenous leukemia and treatmentinduced neutropenia [303]. These abnormalities of uncertain background and significance were thought to represent drug toxicity.

31.4.15 Dasatinib Dasatanib is a multitargeted inhibitor of bcr-abl and SRC family tyrosine kinases that is approved for rescue therapy in patients with imatinib-resistant chronic myelogenous leukemia, and it is also used when imatinib induces adverse effects. The drug is known to cause pleural effusions in 10–35% of patients who receive it [304, 305]. The effusion was an exudate in 78% of the assessable cases [306]. Dasatinib may also cause lung injury in the form of pulmonary infiltrates [32]. In 40 patients on dasatinib, 6 had a lymphocyte predominant pleural exudates, and 7 had parenchymal ground-glass or alveolar opacities or septal thickening [32]. Lymphocytes represented up to 92% of the cells in the BAL, and lymphocytes were confirmed in pleural tissue in one case. Upon dasatinib discontinuance (with corticosteroid therapy in one patient), manifestations of the disease abated or resolved in all nine cases. Interestingly, no relapse occurred in three of four rechallenged patients [32], enabling resumption of treatment with this often vital drug. Lymphocyte-rich effusions (bilateral in one case) were also reported in two patients [304]. Chylous fluid was present in one patient. The authors suggested that the effusions were the result of PDGFR inhibition [304]. Dasatinib 100 mg once daily instead of the classic 70 mg twice daily retains efficacy and reduces toxicity with reduced incidence of pleural effusions from 16%  to 7% [307]. With the better delineation of

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d­ asatinib-induced pleuropulmonary toxicity, noninvasive diagnosis and management should enable cost containment of this adverse effect [308].

31.4.16 Deferoxamine Deferoxamine is used to treat iron overload in transfusion-dependent thalassemia. When given in high dosages or over more than 24 h, deferoxamine may cause diffuse alveolar damage or pulmonary edema [309]. IgE-coated mast cells were evidenced in lung tissue [310]. Rarely, deferoxamine triggers an anaphylactic reaction [311]. No recent case has been published.

31.4.17 Etoposide The podophylotoxin derivative etoposide (VP16-213) is part of conditioning regimens for stem cell transplantation, and the drug is used in the management of refractory Hodgkin’s lymphoma. Pulmonary reactions are of the hypersensitivity type, with suggestive chronology, facial flushing, wheezing, and hypotension [141]. Prudent rechallenge with the drug can be attempted and was successful in up to three quarters of cases [135]. Very few patients with presumed etoposide pneumonitis have been described. The histopathological features may include diffuse alveolar damage, alveolar hemorrhage, and type II cells reactive changes [312].

31.4.18 Fludarabine Fludarabine monophosphate, the 2-fluoro, 5¢ phosphate derivative of 9-beta-d-arabinofuranosyl adenine (ara-A), is a purine analogue used in the treatment of a variety of hematologic malignancies, including chronic lymphatic leukemia, other low-grade non-Hodgkin’s lymphoma resistant to alkylating agents, and acute leukemias. Acute interstitial pneumonitis due to fludarabine was first described in 1987 [313]. The disease improved on high-dose steroids, recurred with steroid withdrawal, and abated with further steroid therapy [313]. Fludarabine pneumonitis can occur as early as

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7 days into treatment, with an incidence rate of 1–8.6% [314]. Patients with a background of chronic lymphatic leukemia and preexisting interstitial pulmonary opacities may be at higher risk of developing pulmonary toxicity [315, 316]. On pathology, cellular interstitial pneumonia, eosinophilic pneumonia, granulomas, BOOP, and DAD with reactive type II cell changes have been described [316, 317]. Fludarabine pneumonitis can occasion severe symptoms and can be fatal [318]. In most cases, symptoms abate with drug removal and corticosteroid therapy. Rechallenging the patient leads to recurrence of manifestations of the ­disease [316, 318].

31.4.19 Gemcitabine Gemcitabine (2,2-difluorodeoxycytidine) is a deoxycytidine analog with structural similarities to cytosine arabinoside. The drug is to treat several hematologic and nonhematologic malignancies, including malignant lymphoma and lung cancer. The first description of gemcitabine pulmonary toxicity was in 1997 in the form of noncardiac pulmonary edema, ARDS, and alveolar hemorrhage in three patients, and corticosteroid therapy was effective in reversing symptoms [92]. Thirty-one reports of gemcitabine pulmonary toxicity were available in the literature in 2006, and there were 147 other unpublished reports gathered in the RADAR project [319]. The incidence of gemcitabine pulmonary toxicity is 0.02–3% [122, 320, 321]. Gemcitabine pulmonary toxicity may develop after one or several courses with the drug, with a mean time to onset of 48 days (range 1–529 days). Drugs that cause pulmonary injury such as bleomycin or docetaxel may synergize gemcitabine pulmonary toxicity [319]. The incidence of gemcitabine pulmonary toxicity was 22% when the drug was added to bleomycin, doxorubicine, and vinblastine in a phase I/II trial in end-stage Hodgkin’s disease [75]. Combining gemcitabine and docetaxel induced a 37% incidence rate of pneumonitis [322]. In yet another study where gemcitabine was added to doxorubicin, bleomycin and vinblastine for the treatment of de novo Hodgkin disease, the incidence of pulmonary toxicity was 41.7% [74]. In a recent study, gemcitabine given with the anti-CD30 antibody VGN-30 was associated in a 31% rate of pulmonary toxicity [323]. Whether and to what extent pulmonary toxicity in these studies

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is due to gemcitabine or to the coadministered drugs is unclear. Gemcitabine potentiates the adverse effects of radiation therapy [324]. Gemcitabine pulmonary toxicity manifests with cough, dyspnea, and fever in the context of diffuse bilateral ground-glass or denser shadowing with or without pleural effusion. Features consistent with capillary leak such as weight gain and lower extremity or generalized edema can be present [122]. On HRCT, the appearances of gemcitabine pulmonary toxicity include inter- and intralobular thickening, groundglass opacities, and pleural effusions. Histopathological appearances include alveolar edema, hyaline membranes, diffuse alveolar damage, and accelerated lung fibrosis, whereas alveolar hemorrhage, interstitial pneumonia, and reactive type II cells are less common features [92, 325–327]. Corticosteroids were used with benefit in several cases. Mortality is about 20% [328]. Rechallenge with the drug produces relapse of symptoms [329] and may occasion fatal respiratory failure [92]. Gemcitabine pulmonary toxicity may also manifest in the form of the hemolytic and uremic syndrome (HUS). Presenting features include systemic hypertension, anemia, thrombocytopenia, hematuria, renal failure, and circulating schizocytes. The incidence is up to 2.2%, and 35 cases were reviewed [330]. Subclinical HUS has been described, and monitoring of hemoglobin, creatinine, and circulating schizocytes is advised in patients who have received the drug.

31.4.20 Hydroxyurea Eleven cases of hydroxyurea-induced pneumonitis were reviewed in 2003 [331]. The pulmonary reaction developed after 3–12 weeks on the drug in the form of fever and bilateral reticular or nodular infiltrates, and a small pleural effusion was present in five cases. Rechallenge with the drug was followed by recurrence. Outcome is good [331].

31.4.21 Interferon Interferon (IFN) alpha and beta are a therapeutic option in patients with chronic myelogenous

31  Pleuropulmonary Changes Induced by Drugs in Patients with Hematologic Diseases

leukemia, myeloma, and myelofibrosis, in addition to their established use for the treatment of chronic hepatitis C virus infection and multiple sclerosis. Interferon gamma has been used experimentally as a salvage therapy of corticosteroid-resistant pulmonary toxicity syndrome following BCNU-based chemotherapy and met with limited success in the treatment of pulmonary fibrosis. The respiratory complications from IFN (mostly alpha 2b [332]) may be dose-dependent and occur more commonly following the use of pegylated IFN, and may develop regardless of the underlying disease for which IFN is given. However, most reports are in patients with hepatitis C virus infection [333]. The most distinctive adverse effect of IFN alpha and beta is a picture indistinguishable from naturally occurring sarcoidosis. After a few months into treatment, patients develop de novo sarcoidosis or there is reactivation of previously diagnosed quiescent sarc­ oidosis. The lung, liver, heart, central nervous system, and skin can be involved [333], and hypercalcemia has been reported [334]. On imaging, IFN-induced sarc­ oidosis-like disease is in the form of hilar or mediastinal lymphadenopathy, ground-glass shadowing, micronodular infiltrates, or thickening along the bronchovascular bundles [335]. Increased lymphocytes, generally of the CD8+ phenotype, are present in the BAL [335, 336], and this is at variance with the findings in naturally occurring sarcoidosis. Eighty-five percent of patients stabilize or improve, 15% develop chronic stable disease, and a third require corticosteroid ­treatment [333]. Interferons can induce other forms of ILD. Interferon therapy may induce volume loss with a disproportionate decrease of diffusing capacity for CO and no discernible pulmonary opacities [337, 338], cellular interstitial pneumonia, ARDS [339], desquamative interstitial pneumonia [340], pulmonary fibrosis [340], eosinophilic pneumonia [341], and BOOP [342]. The latter condition may manifest with diffuse infiltrates [343, 344] or a mass [64]. Most cases of IFN-induced interstitial lung disease respond to diminution of drug dosage, drug removal, and corticosteroid therapy [336]. A recent review of 25 published cases showed onset of the disease after 23  days to 10  months into treatment [332]. There was one fatality [332]. Other adverse effects of IFN include lone dyspnea, chronic cough [345], exacerbation of asthma [346], pleural effusion [347], pulmonary hypertension [348], and drug-induced lupus [349].

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31.4.22 Imatinib Imatinib is a protein kinase inhibitor that downregulates the Bcr-Abl protein kinase generated by the Philadelphia chromosome in chronic myelogenous leukemia. Pneumonitis [17, 350], fluid retention, and pleural effusion [351] have been reported during treatments of chronic myelogenous leukemia with the drug. A series of 27 interstitial pneumonitis cases (with a preponderance of males) was published in 2006 [17]. Onset of the disease was after a median of 49 days into treatment with no evidence that drug dosage was playing a role. Clinical presentation included dyspnea and hypoxemia. Histopathological findings included interstitial inflammation, fibrosis, organizing pneumonia, and eosinophilic pneumonia, and a reactive epithelium [17]. Drug lymphocyte stimulation test was negative in all nine patients so tested [17]. The drug was withdrawn in all patients, and most patients received corticosteroid therapy to alleviate symptoms. The condition resolved in seven patients and improved in 16. In the 11 patients who were rechallenged, the disease relapsed in only 4, an important consideration regarding the management of the native hematologic malignancy. One patient was successfully rechallenged while receiving 60 mg of prednisolone [352]. At least seven cases of imatinib-induced pneumonitis with or without fluid retention and pleural effusion have been reported in the interim of the above report [17]. One case of eosinophilic pneumonia ascribed to this agent is available [353], and pulmonary alveolar proteinosis developed in another patient [354].

31.4.23 Lenalidomide Three cases of lenalidomide-induced pneumonitis have been reported in patients with multiple myeloma. Lymphocytes were increased in the BAL two cases. Pathology disclosed interstitial pneumonia and granulomas and BOOP in one case each [55, 355–358].

31.4.24 Melphalan Meplhalan produces epithelial changes in the lung that resemble those of other alkylating agents [359]. There are

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not many well-documented cases of melphalan-induced pneumonitis [360–362]. The condition typifies the chemotherapy lung. In early cases, the disease is acute and reverses with drug withdrawal and corticosteroid therapy [361]. Later cases present with the features of late chemotherapy lung, i.e., lung fibrosis and reactive type II cell changes [363]. Corticosteroids are indicated and have reversed late melphalan toxicity [362].

31.4.25 Methotrexate Methotrexate lung can complicate treatments of various neoplastic and nonneoplastic conditions (mainly rheumatoid arthritis nowadays) in 0.86–6.9% of patients on the drug [364]. Risk factors in rheumatoid arthritis include prior ILD, advanced age, diabetes mellitus, and low serum albumin. A previous episode of methotrexate pneumonitis is the strongest risk factor for relapse, should the patient be reexposed to the drug. The first report of methotrexate pneumonitis dates back 41  years [365]. Acute pulmonary disease developed in seven children in clinical remission from their hematologic malignancy. The disease was life threatening in six. Open lung biopsy showed interstitial pneumonitis with granuloma formation. Cessation of the drug and corticosteroid therapy were effective with a return to normal in 10–40  days. Methotrexate could be continued in some patients. In 2000, 123 cases of methotrexate lung in hematology